Policies for Rare Diseases and Orphan Drugs - KCE

Policies for Rare Diseases and Orphan 

Drugs 

KCE reports 112C 

Federaal Kenniscentrum voor de Gezondheidszorg 

Centre fédéral d’expertise des soins de santé 

Belgian Health Care Knowledge Centre 

2009

The Belgian Health Care Knowledge Centre 

Introduction : The Belgian Health Care Knowledge Centre (KCE) is an organization 

of public interest, created on the 24 th of December 2002 under the 

supervision of the Minister of Public Health and Social Affairs. 

KCE is in charge of conducting studies that support the political 

decision making on health care and health insurance. 

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Vermeyen Karel, Kesteloot Katrien, Ooghe Bart, Lernoux Frederic, 

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Catherine. 

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Policies for Rare Diseases and 

Orphan Drugs 


ALAIN DENIS, STEVEN SIMOENS, CHRISTEL FOSTIER, LUT MERGAERT, IRINA CLEEMPUT 

Federaal Kenniscentrum voor de Gezondheidszorg 

Centre fédéral d’expertise des soins de santé 

Belgian Health Care Knowledge Centre 

2009


Title : Policies for Rare Diseases and Orphan Drugs 

Authors : Alain Denis (Yellow Window Management Consultants), Steven Simoens 

(K.U.Leuven), Christel Fostier (Yellow Window Management 

Reviewers: 

Consultants), Lut Mergaert (Yellow Window Management Consultants), 

Irina Cleemput (KCE) 

Mattias Neyt (KCE), Frank Hulstaert (KCE) 

External experts : Jean-Jacques Cassiman (K.U.Leuven/U.Z. Leuven), Marc Dooms 

Acknowledgements 

(K.U.Leuven/U.Z. Leuven), François Eyskens (University of Antwerp), 

André Lhoir (FAGG/AFMPS), Philippe Van Wilder (RIZIV/INAMI) 

We would like to thank the EMEA and Hans-Georg Eichler in particular 

for the fruitful collaboration on part of this project and Frank Hulstaert 

for review of the EMEA files. The study team also wants to thank 

explicitly Marc Dooms for his valuable contribution and availability 

throughout the study period. 

External validators: Gepke Delwel (College voor Zorgverzekeringen (CVZ), the 

Conflict of interest: 

Netherlands), Alastair Kent (Genetic Interest Group, UK), Marc Bogaert 

(U.Z. Gent) 

François Eyskens received a fee for participating in the International Fabry 

Expert Group which was logistically supported by Shire (October 2008) 

and was reimbursed by Shire as the organizer of the Fabry disease 

symposium in Mexico (October 2008). Marc Bogaert is chairman of the 

College for physicians for orphan drugs at the National Institute for 

Health and Disability Insurance. Alastair Kent received reimbursement of 

expenses from Genzyme to support participation as a speaker at a 

conference and to chair a panel discussion at a conference. 

Disclaimer: The external experts were consulted about a (preliminary) version of the 

scientific report. Subsequently, a (final) version was submitted to the 

validators. The validation of the report results from a consensus or a 

voting process between the validators. Only the KCE is responsible for 

errors or omissions that could persist. The policy recommendations are 

also under the full responsibility of the KCE. 

Layout: Ine Verhulst 

Brussels, 19 th February 2010 (2 nd print; 1 st print: 9 th July 2009) 

Study nr 2008-04 

Domain: Health Technology Assessment (HTA) 

MeSH: Rare Diseases; Orphan Drug Production; Health Policy; Legislation, Drug 

NLM classification : QZV 736 

Language: English 

Format: Adobe® PDF (A4) 

Legal depot: D/2009/10.273/32 

How to refer to this document? 

Denis A, Simoens S, Fostier C, Mergaert L, Cleemput I. Policies for Rare diseases and Orphan Drugs. 

Health Technology Assessment (HTA). Brussels: Belgian Health Care Knowledge Centre (KCE); 2009. 

KCE reports 112C (D/2009/10.273/32)

KCE reports 112C Orphan drugs i 

Executive summary 

BACKGROUND AND AIMS OF THE STUDY 

METHODS 

Due to low prevalence, rare diseases have traditionally been neglected by industry and 

by the scientific, medical and political communities. It is estimated that there are 

currently between 5000 and 7000 different rare or rare diseases. Both in the United 

States (US) and in the European Union (EU), schemes were launched to stimulate the 

development of ‘orphan drugs’, drugs developed to treat these rare diseases. The 

rationale behind these legislations is to compensate industry for the risks and lower 

potential return on investment as a consequence of the inherently low number of 

patients. These schemes are considered as a success with an increasing number of 

Orphan Designation requests filed at the US Food and Drug Administration (FDA) and 

the European Medicines Agency (EMEA). Orphan Designation refers to granting the 

orphan status to a medicinal product, while Marketing Authorisation refers to the 

approval to bring the product to the market. Since the development of the regulation to 

promote research and development on orphan drugs in the EU in 2000, 522 drugs 

obtained Orphan Designation and 47 received Marketing Authorisation. 

While Orphan Designation and Marketing Authorisation for these orphan drugs are 

decisions taken at the EU level, the drug reimbursement decision is a member state 

(MS) responsibility. National drug reimbursement committees (DRCs) are facing the 

trend of the increasing number of new orphan drugs entering the market and expect a 

relative increase in the budget spent on orphan drugs as compared to drugs for more 

common diseases mainly because of the high prices charged for these orphan drugs. 

This study’s objectives are to: 

1. provide an overview of the commonly used definitions for ‘rare diseases’ and 

‘orphan drugs’ and describe the particularities of orphan drugs as compared 

to drugs for regular diseases; 

2. describe the regulatory processes for orphan drugs from Orphan Designation 

to reimbursement; 

3. compare the Belgian orphan drug reimbursement policy with other countries; 

4. estimate the current budget impact of orphan drugs and forecast the 

expected future budget impact; 

5. formulate recommendations for policy makers concerning orphan drugs. 

A narrative review, based on regulatory documents and published articles, provides an 

overview of the definitions for rare diseases and orphan drugs. For the description of 

regulatory processes for orphan drugs regulatory documents were examined and 

interviews performed with experts and key actors involved in the processes, both at 

national level and at European level (EMEA). Representatives of various stakeholders, 

including the pharmaceutical industry, patient organisations, policy makers, and experts 

involved in the assessment of orphan drug files were interviewed. 

To examine the consistency of the information provided by industry to the different 

authorities at different levels and the extent to which information available at European 

level could be used or be made more useful for national DRCs, a comparison was made 

between the clinical files submitted to the EMEA for obtaining marketing Authorisation, 

the resulting European Public Assessment Reports (EPARs) and the clinical evidence 

submitted to the Belgian National Institute for Health and Disability Insurance (NIHDI) 

as part of a drug reimbursement request. This was done for 15 specific drug-indication 

combinations. This collaboration between the EMEA and a national Health Technology 

Assessment (HTA) agency was unique and shows that it can serve a mutual interest, 

especially concerning orphan drugs.

ii Orphan drugs KCE reports 112C 

Additionally, a critical appraisal was made of the clinical and economic evidence 

submitted to the Belgian DRC for 8 cases. These were not necessarily included in the 

15 cases examined at the EMEA. The critical appraisal mainly looked at the type and 

level of evidence submitted as well as the methodological standards applied to drug 

reimbursement files for orphan drugs. 

Six countries were included in the cross-country comparison of orphan drug 

reimbursement procedures: Belgium, France, Italy, the Netherlands, Sweden and the 

United Kingdom. The country comparison relied on grey literature as well as on a 

survey among experts of the respective countries. 

For all reimbursed orphan drugs in Belgium the budget impact was estimated based on 

information in the reimbursement request file and publicly available information. In 

addition, simulations of the expected future budget impact of orphan drugs were made, 

using as a basis the average number of orphan drugs receiving marketing Authorisation 

each year, the proportion of orphan drugs obtaining reimbursement in Belgium and the 

average yearly orphan drug cost per patient. 

DEFINITIONS AND PARTICULARITIES OF ORPHAN DRUGS 

In the European legislation a rare disease is defined as a life-threatening or chronically 

debilitating condition with a prevalence of 5 patients per 10 000 people or less. 

However, a variety of definitions of rare diseases and of orphan drugs is used in the 

legislation of various countries. 

Also, a number of challenges exist with respect to the development, Marketing 

Authorisation, pricing, reimbursement and post-marketing follow-up of orphan drugs. 

Because of the low prevalence of these diseases, the development of a treatment is 

usually not considered economically interesting for a company. This situation might 

create unequal access to treatment between patients suffering from an rare disease and 

patients suffering from a more common disease. Therefore, the EU has created a series 

of incentives for the development of orphan drugs, such as fee reductions, protocol 

assistance and 10 years of market exclusivity. 

Orphan drugs are usually expensive. Considering all orphan drugs reimbursed in 

Belgium in 2008, the cost per patient per year was estimated to range from €6000 (for 

the treatment of gastro-intestinal stromal tumour) to €312 000 (for the treatment of 

mucopolysaccharidosis type I). Companies justify these high prices by claiming that the 

high costs of research and development for orphan drugs can only be recouped from a 

small number of patients by asking higher prices. An additional explanation might be the 

monopoly situation that emerges when there are no alternative treatments yet for a 

specific rare condition and when, at the same time, no Marketing Authorisation can be 

granted to a similar product for the same therapeutic indication. It is worth noting that 

some products that were originally approved as orphan drugs and as such benefited 

from special measures later became top sellers, either because the indications were 

extended to more common diseases or because the rare indication became more 

frequent.

KCE reports 112C Orphan drugs iii 

ORPHAN DESIGNATION AND MARKETING 

AUTHORISATION 

To qualify for the special regulatory arrangements for orphan drugs, a drug has to 

obtain the orphan status through the Orphan Designation procedure at the EMEA. 

Afterwards, when the drug is ready for market introduction, Marketing Authorisation 

can be requested. At the EMEA two separate committees are responsible: the 

Committee for Orphan Medicinal Products (COMP) and the Committee for Human 

Medicinal Products (CHMP) respectively. 

Orphan Designation is subject to two conditions: 

• the medicinal product is intended for the diagnosis, prevention or 

treatment of a life-threatening or chronically debilitating condition that 

either affects less than 5 in 10 000 persons of the Community; or that 

without incentives is unlikely to generate sufficient return on investment 

to justify the expenditure; 

• there is an absence of solution or the drug brings a significant benefit 

compared to the present situation. 

The EMEA criteria used for Orphan Designation are different from the FDA’s. The FDA 

also considers the prevalence criterion, but more from the perspective of economic 

viability than from the perspective of existing alternatives. In the US, Orphan 

Designation cannot be reconsidered, whereas it can in the EU. The FDA grants market 

exclusivity for 7 years. 

In contrast to many of the other drugs, where a national procedure still exists for 

obtaining Marketing Authorisation, since 2005 orphan drugs can only obtain Marketing 

Authorisation through the centralized procedure at the EMEA. A Marketing 

Authorisation request is assessed by the CHMP supported by the preparatory work of 

the rapporteurs and their teams. The CHMP gives an opinion to the European 

Commission, which finally decides on the Marketing Authorisation. Based on the CHMP 

assessment report a European Public Assessment Report (EPAR) is prepared and 

published on the web-site of the EMEA. 

A drug cannot receive Marketing Authorisation for an rare indication and a non-rare 

indication. In case of a conflict, the rare indication has to be dropped or marketing 

Authorisation will have to be requested for the drug under a different name. 

Consequently, identical products can be brought to the market under different names 

and prices. 

A company can decide to make a drug that has not yet obtained Marketing 

Authorisation but that is being considered by the EMEA, available on the market under 

the format of a ‘compassionate use programme’. The rules and conditions of the 

compassionate use programmes are organized either at the European level by the EMEA 

or at the national level by the individual member states.

iv Orphan drugs KCE reports 112C 

ORPHAN DRUG REIMBURSEMENT IN BELGIUM 

Drug reimbursement decisions are taken by the Minister of Social Affairs, after advice 

from the Drug Reimbursement Committee (DRC). Orphan drugs follow the same 

procedure as Class I pharmaceutical products, i.e. products for which the company 

claims a therapeutic added value. However, unlike for Class I pharmaceutical products, 

no pharmacoeconomic evaluation has to be submitted for orphan drugs. A decision on 

the reimbursement is taken within 180 days following the submission of the 

reimbursement request. 

At the end of December 2008, 31 orphan drugs were reimbursed in Belgium (including 

two products that do not have orphan drug status, but reimbursed for an rare 

indication) for a total of 35 rare indications. Orphan drugs are fully reimbursed. 

The prescription and individual reimbursement of orphan drugs is subject to conditions. 

The treating specialist physician must first obtain the approval of a Medical Advisor of 

the patient’s sickness fund to prescribe the medicine. The Medical Advisor can, but is 

not obliged to, request the advice of a “College of Medical Doctors for Orphan Drugs” 

(CMDOD). In practice, all sickness funds have agreed to refer all requests to the 

CMDOD if one exists. Separate Colleges exist for separate products. It is the DRC that 

decides whether or not a College is established. Individual reimbursement decisions are 

taken on a case by case basis by the CMDOD. At the end of 2008, there were 18 

colleges for 18 out of the 31 orphan drugs. 

If a medicinal product is not yet on the Belgian list of reimbursed pharmaceutical 

products, the patient may be able to benefit from a compassionate use or medical need 

programs by the company or in case the drug is already available on the market, request 

reimbursement through the Special Solidarity Fund (SSF). Conditions for compassionate 

use or reimbursement through the SSF are defined by law. In 2007, orphan drugs 

accounted for about 35% of the SSF’s total budget. 

INTERNATIONAL COMPARISON 

As in France, Italy and Sweden, Belgium has a number of centres of reference for rare 

diseases that are recognized by the NIHDI. Belgium has 8 centres for human genetics, 

10 centres for monogenic metabolic disorders and 6 centres for neuromuscular 

disorders, although these centres are not completely comparable to the centres of 

excellence in other countries. However, no formal network of centres for rare diseases 

exists in this country. Centres of reference can build up expertise in specific rare 

diseases more easily than in cases where patients remain scattered over the country. 

In comparison with other countries, national measures to promote research on orphan 

drugs are relatively limited in Belgium. Sales of orphan drugs are exempted from taxes 

but no formal research or support programmes are developed like in France, Italy and 

the Netherlands. 

Most countries, except for Sweden and the UK, compare the price requested by the 

company to the price in other countries. This creates incentives for the companies to 

introduce their products first in countries where a price requested as well as 

reimbursement are relatively easy to obtain compared to other countries. The UK has 

set up a system of profit control to control prices and Sweden uses a system of 

negotiation at the regional level. 

In Belgium and the UK, the distribution of orphan drugs occurs through hospital 

pharmacies only, although no formal prohibition exists against the sales of orphan drugs 

in open pharmacies. In the other countries orphan drugs can also be delivered through 

community pharmacies. In Belgium, the UK and Italy prescription of orphan medication 

is the exclusive responsibility of a specialist physician. In all countries, specific conditions 

apply to the prescription of orphan drugs. An interesting case in this respect is Italy, 

where an orphan drug for an individual patient can only be delivered upon registration 

of the treatment start and follow-up in a national disease registry.

KCE reports 112C Orphan drugs v 

EVIDENCE LEVELS IN REIMBURSEMENT FILES 

To obtain reimbursement of an orphan drug, companies have to submit evidence on the 

efficacy and preferably also on the effectiveness of the drug as well as a budget impact 

analysis to the DRC. 

The evidence on clinical effectiveness is typically limited for orphan drugs, especially for 

drugs targeting extremely small groups of patients. Due to the small number of patients 

clinical studies are rarely sufficiently powered to detect significant results on hard 

clinical endpoints. Moreover, the natural history of the disease is usually unknown, as 

physicians only have limited experience with the disease. The level of evidence in 

orphan drug reimbursement requests is therefore generally low. However, for nearly all 

products we examined at least one randomized controlled trial (RCTs) was performed 

demonstrating the possibility to perform RCTs for orphan drugs. 

With respect to the choice of the comparator, it has been observed that alternative 

treatments were available for 15 orphan drugs, and that different orphan drugs 

sometimes have the same indication. 

Budget impact analyses in drug reimbursement files are often incomplete, in that they 

do not account for the budgetary impact of the product in the different indications for 

which the product can be used. Companies can submit separate files for separate 

indications, in which case they calculate the budget impact of the indication for which 

the request is submitted, while the DRC should be able to consider the total budget 

impact of successive reimbursement files of an orphan drug relating to different 

indications. Methodological guidelines for budget impact analyses do not exist yet. 

CLINICAL INFORMATION AT DIFFERENT LEVELS 

The clinical file submitted to the EMEA in the context of a Marketing Authorisation 

request is not available for the DRCs of the member states, but a public assessment 

report (EPAR) is published for drugs that obtained Marketing Authorisation. The Belgian 

DRC asks companies to send the end-of-study reports as part of their drug 

reimbursement request file. Although companies are not obliged to do this, they usually 

provide these reports. 

The information from the clinical files submitted to the EMEA is generally wellrepresented 

in the EPARs, although some suggestions could be made to further 

improve the utility of the EPARs for the national DRCs. For some drugs, a selective 

representation of the study results was found in the drug reimbursement request file: 

absence of the results of a negative study, of a phase I/II study and of an extension study 

and a vague description of the improvement without mentioning that these results were 

not significant from a statistical point of view. In 4 of the 15 examined cases more 

information was provided in the NIHDI file than was available in the EMEA file, which 

can be explained by the time lag between the Marketing Authorisation request and the 

drug reimbursement request. 

Another observation is that an orphan drug may receive approval under exceptional 

circumstances based on surrogate endpoints only. In such cases the information 

included in the EPAR, may not be relevant as such for the national decision maker, since 

the decision maker is mostly interested in clinically relevant outcomes parameters. In 

such cases the EMEA may request an additional RCT including these hard endpoints as a 

postmarketing requirement. Unfortunately, the results of such studies are not always 

made public by the EMEA and the EPAR is not automatically updated.

vi Orphan drugs KCE reports 112C 

BUDGET IMPACT ANALYSIS AND FORECAST 

The NIHDI expenditures on orphan drugs in Belgium is estimated to have been about 

€66 million or over 5 % of total hospital drug budget in 2008 and further estimates 

indicate the future cost will be well above 10 % of hospital drug budget in five years 

from now. Orphan drugs represent probably 2% of total drug reimbursement 

expenditures by NIHDI in 2009, and are estimated to represent close to 4% in 2013. 

This increasing cost creates an additional upward pressure on health care budgets and 

may challenge the limits of solidarity between citizens. 

The high prices combined with the growing budget impact of orphan drugs also 

negatively affect the image of the orphan drugs among decision-makers. 

RECOMMENDATIONS 

EUROPEAN RECOMMENDATIONS 

Disease and patient registries 

• Priorities for research on rare diseases should be defined on European 

level in order to target public research funds for research and 

development of orphan drugs. 

• For the high priority rare diseases, Europe should invest in setting up 

registries as early as possible; preferably before a drug is being developed 

for the disease. Data on the natural history of the disease and baseline 

risks are indispensable for describing the epidemiology of the disease and 

put into context the clinical effectiveness of a treatment. The Directive 

95/46/EC of the European Parliament and of the Council of 24 October 

1995 on the protection of individuals with regard to the processing of 

personal data and on the free movement of such data should be respected 

when setting up these registries and using their data. 

• HTA agencies could play a role in the design of patient registries to 

ensure that the data collected can be used to help appreciate the 

effectiveness and cost-effectiveness obtained for novel drugs. 

• The aggregated data from the registries should be publicly available. 

• Funding and governance of the registries should be independent from the 

company developing an orphan drug. Innovative models combining 

European and national funds could be explored to set up such a system, 

the beneficiaries being the companies considering the clinical development 

of an orphan drug, the medicine agencies in assessing efficacy and safety, 

the national health care insurance funds, and the patients.

KCE reports 112C Orphan drugs vii 

Orphan drug designation and marketing authorisation 

• Evidence from Randomized Controlled Trials (RCTs) with clinically 

relevant endpoints should remain the standard for granting marketing 

authorization. The clinical endpoints should also have relevance for 

national reimbursement decisions. 

• Surrogate outcome measures should only be used if there is a clear link 

with final endpoints or when final outcomes cannot be measured over an 

acceptable period of time. 

• HTA agencies may provide valuable input at the EMEA level for the 

definition of the endpoints needed and level of clinical improvement 

required in phase 3 studies, such that the product would qualify for 

reimbursement. 

• The criteria for obtaining the orphan drug status and the associated 

incentive mechanisms may have to be revised in order to avoid artificial 

sub-setting. 

• The marketing exclusivity period should be revised when a product turns 

out to be profitable after a specific period of time, considering all 

indications of the drug. EU regulation should define what profitability 

means as well as the period of time over which profitability is assessed. 

• The European Public Assessment Reports (EPARs) should always 

o include a standard and complete tabular overview of clinical trials 

which were performed or are still ongoing, mentioning the primary 

endpoints and the results for the pre-defined analyses, along with 

their level of significance 

o be updated whenever new evidence becomes available from 

studies requested by the EMEA in case of marketing Authorisation 

under exceptional circumstances. 

NATIONAL RECOMMENDATIONS 

Reimbursement policy 

• A drug reimbursement request file for an orphan drug should contain the 

same elements as a reimbursement request file for a class 1 

pharmaceutical product, more specifically: 

o At least efficacy, but preferably effectiveness, on a clinically relevant 

outcome should be demonstrated. 

o Cost-effectiveness ratios should be presented to show what 

society is paying for a Quality Adjusted Life Year (QALY) or life 

year gained. 

o Budget impact analysis should be based on epidemiological data 

from registries. 

o Standardised cost information submitted to the Federal Public 

Service Economy in the context of pricing. This standardisation has 

yet to be realised.

viii Orphan drugs KCE reports 112C 

Price setting and budget impact control 

Centralisation of Prescription requests 

• Price setting would ideally be dealt with at the European level or 

coordinated between member states. 

• In the meantime, NIHDI might consider different options to control the 

prices of orphan drugs: 

o Requiring a justification for the price based on detailed information 

on the investments made and the potential return at a global level. 

This should be accompanied by a regular monitoring. 

o Risk-sharing between the drug company and the public payer, 

based on price for performance or conditional reimbursement. 

The minimally expected level of effectiveness on specific endpoints 

and the consequence of not realising the expected result, should 

be clearly specified when risk-sharing schemes are envisaged. 

• If a product is already reimbursed other indications, the budget impact of 

the product for those indications should also be reported. 

• All requests for the reimbursement of an orphan drug for an individual 

patient should be submitted directly to one central counter organised by 

the secretariat of the DRC at the NIHDI. This secretariat needs to be 

reinforced if charged with this additional task. 

• Reimbursement of an orphan drug for a particular patient should be 

conditional upon the delivery of the standardised information for the 

patient registry. 

• For each of the orphan drugs, the secretariat composes a College 

consisting of a representative from the secretariat and external experts 

that are chosen for their expertise in the rare disease. The secretariat 

delivers the prescription requests to the appropriate college. 

• The secretariat should make sure that the reimbursement criteria are 

consistently applied and should centralise the registration data of all 

reimbursement requests as well as the decisions of the Colleges. It should 

publish these data to increase the transparency of the system, conform 

the privacy law. 

• The secretariat should also act as a coordination centre for rare diseases. 

It should be able to refer a physician who is faced with a patient with an 

rare disease to an appropriate expert or reference centre. A central 

website with appropriate information and links for all rare diseases and 

orphan drugs would be of use in this context.

KCE Reports 112 Orphan Drugs 1 

Scientific Summary 

Table of contents 

GLOSSARY ................................................................................................................................. 4 

1 INTRODUCTION ............................................................................................................ 6 

1.1 OBJECTIVES OF THIS STUDY .................................................................................................................. 7 

1.2 GENERAL METHODOLOGY OF THE STUDY ................................................................................... 7 

2 ORPHAN, RARE AND NEGLECTED DISEASES AND DRUGS: DEFINITIONS 

AND PARTICULARITIES ............................................................................................... 9 

2.1 INTRODUCTION ........................................................................................................................................ 9 

2.2 METHODOLOGY ........................................................................................................................................ 9 

2.3 ORPHAN, RARE AND NEGLECTED DISEASES AND DRUGS ....................................................... 9 

2.4 ORPHAN DRUGS ...................................................................................................................................... 10 

2.4.1 Background ...................................................................................................................................... 10 

2.4.2 Definitions ........................................................................................................................................ 11 

2.4.3 Development ................................................................................................................................... 11 

2.4.4 Marketing Authorisation ............................................................................................................... 12 

2.4.5 Pricing ............................................................................................................................................... 13 

2.4.6 Health technology assessment and reimbursement ................................................................ 14 

2.5 CONCLUSIONS ......................................................................................................................................... 15 

3 POLICY DESCRIPTION ............................................................................................... 17 

3.1 INTRODUCTION ...................................................................................................................................... 17 

3.2 EMEA PROCESS: FROM ORPHAN DESIGNATION TO MARKETING AUTHORISATION . 17 

3.2.1 Presentation of EMEA ................................................................................................................... 17 

3.2.2 Applying for Orphan Designation ............................................................................................... 18 

3.2.3 Applying for Marketing Authorisation ....................................................................................... 22 

3.2.4 Compassionate use ........................................................................................................................ 28 

3.3 FDA PROCESS: FROM ORPHAN DESIGNATION TO MARKETING AUTHORISATION .... 28 

3.3.1 Presentation of the FDA ............................................................................................................... 28 

3.3.2 Orphan Drug Designation ............................................................................................................ 29 

3.3.3 Marketing approval ........................................................................................................................ 31 

3.3.4 Compassionate use ........................................................................................................................ 31 

3.4 EMEA-FDA COMPARISON ..................................................................................................................... 31 

4 INTERNATIONAL COMPARISON OF RARE DISEASE AND DRUG MARKETS 

IN EUROPE .................................................................................................................... 34 

4.1 INTRODUCTION ...................................................................................................................................... 34 

4.2 METHODOLOGY ...................................................................................................................................... 34 

4.3 BELGIUM ...................................................................................................................................................... 35 

4.3.1 Institutional context ....................................................................................................................... 35 


4.3.3 Reimbursement ............................................................................................................................... 36 

4.3.4 Pricing ............................................................................................................................................... 43 

4.3.5 Distribution ..................................................................................................................................... 43 

4.3.6 Prescribing ....................................................................................................................................... 43 

4.4 FRANCE ....................................................................................................................................................... 45 




4.4.4 Pricing ............................................................................................................................................... 48 

4.4.5 Distribution ..................................................................................................................................... 48 

4.4.6 Prescribing ....................................................................................................................................... 49 

4.5 ITALY ............................................................................................................................................................ 49 


4.5.2 Marketing Authorisation ............................................................................................................... 50

2 Orphan Drugs KCE Reports 112 


4.5.4 Pricing ............................................................................................................................................... 51 

4.5.5 Distribution ..................................................................................................................................... 52 

4.5.6 Prescribing ....................................................................................................................................... 52 

4.6 THE NETHERLANDS ................................................................................................................................ 53 




4.6.4 Pricing ............................................................................................................................................... 58 

4.6.5 Distribution ..................................................................................................................................... 58 

4.6.6 Prescribing ....................................................................................................................................... 58 

4.7 SWEDEN ...................................................................................................................................................... 59 




4.7.4 Pricing ............................................................................................................................................... 61 

4.7.5 Distribution ..................................................................................................................................... 61 

4.7.6 Prescribing ....................................................................................................................................... 61 

4.8 UNITED KINGDOM ................................................................................................................................. 62 




4.8.4 Pricing ............................................................................................................................................... 65 

4.8.5 Distribution ..................................................................................................................................... 66 

4.8.6 Prescribing ....................................................................................................................................... 66 

4.9 COMPARATIVE ANALYSIS ..................................................................................................................... 66 

5 CRITICAL ASSESSMENT ............................................................................................. 70 

5.1 INTRODUCTION ...................................................................................................................................... 70 

5.2 METHODOLOGY ...................................................................................................................................... 70 

5.2.1 Qualitative overview ...................................................................................................................... 70 

5.2.2 In-depth analysis ............................................................................................................................. 71 

5.3 QUALITATIVE OVERVIEW OF ALL REIMBURSEMENT DOSSIERS ............................................. 72 

5.4 IN-DEPTH ANALYSIS OF 15 SELECTED REIMBURSEMENT DOSSIERS ..................................... 74 

5.4.1 Comparison of the evaluations by EMEA .................................................................................. 74 

5.4.2 Comparison of the studies mentioned in the NIHDI file, the EMEA file and EPAR ........ 75 

6 BUDGET IMPACT ANALYSIS .................................................................................... 77 

6.1 METHODOLOGY ...................................................................................................................................... 77 

6.2 BUDGET IMPACT IN BELGIUM AT THE END OF 2008 ................................................................ 77 

6.3 BUDGET IMPACT FORECAST ............................................................................................................... 81 

7 DISCUSSION AND CONCLUSIONS ......................................................................... 85 

7.1 ORPHAN DRUG DESIGNATION AS A TACTICAL STEP ............................................................. 85 

7.2 PREVALENCE VERSUS ECONOMIC MOTIVES ................................................................................. 85 

7.3 ASSESSING CLINICAL ADDED VALUE ............................................................................................... 86 

7.4 THE NEED FOR A RIGHT BALANCE BETWEEN ETHICAL AND ECONOMIC CONCERNS 

........................................................................................................................................................................ 87 

7.5 PRICING ....................................................................................................................................................... 88 

7.6 EXTENSION OF INDICATIONS ........................................................................................................... 91 

7.7 GROWTH OF THE BUDGET IMPACT OF ORPHAN DRUGS ..................................................... 92 

7.8 VARIATIONS IN ACCESS AND USE AMONG MEMBER STATES ............................................... 92 

7.9 AWARENESS RAISING ............................................................................................................................. 94 

7.10 COLLEGES AND CONTROL OF ELIGIBILITY .................................................................................. 94 

7.11 USE OF REGISTRIES .................................................................................................................................. 96 

8 APPENDICES ................................................................................................................. 99


8.1 OVERVIEW REIMBURSED ORPHAN DRUGS IN BELGIUM ........................................................ 100 

8.2 CHARACTERISTICS OF ORPHAN DRUGS SUBMITTED FOR REIMBURSEMENT IN 

BELGIUM, 2004-2008 .............................................................................................................................. 102 

8.3 QUALITATIVE QUESTIONNAIRE BENCHMARKING .................................................................. 104 

8.4 QUALITATIVE QUESTIONNAIRE PHARMACEUTICAL INDUSTRIES ..................................... 108 

8.5 LIST OF EXPERTS AND STAKEHOLDERS CONSULTED FOR THE STUDY ......................... 110 

8.5.1 List of interview respondents .................................................................................................... 110 

8.5.2 Consultations ................................................................................................................................ 110 

8.5.3 National experts ........................................................................................................................... 110 

8.6 LIST OF 14 ORPHAN DRUGS USED FOR EMEA – NIHDI COMPARISON ............................ 111 

9 REFERENCES ............................................................................................................... 112


GLOSSARY 

Afssaps Agence Française de Sécurité Sanitaire des Produits 

de Santé 

http://agmed.sante.gouv.fr/ 

AIFA Agenzia Italiana del Farmaco (Italian Medicines 

Agency) 

http://www.agenziafarmaco.it 

ASMR Amélioration du Service medical rendu 

(Improvement in clinical added value) 

ATC Anatomical Therapeutic Chemical-code 

ATU Authorisation for Temporary Usage 

AWMSG All Wales Medicines Strategy Group http://www.wales.nhs.uk 

BNF British National Formulary 

CBG College ter Beoordeling van Geneesmiddelen (Dutch 

Medicines Evaluation Board) 

http://www.cbg-meb.nl/cbg/nl 

CEPS Comité Economique des Produits de Santé (French 

Healthcare Products Economic Committee) 

http://www.sante.gouv.fr/ceps/ 

CHMP EMEA Committee for Medicinal Products for Human http://www.emea.europa.eu/htms/gen 

Use 

eral/contacts/CHMP/CHMP.html 

CMDOD Belgian College of Medical Doctors for Orphan 

Drugs (College van Geneesheren voor 

Weesgeneesmiddelen / Collège de médecins pour 

des médicaments orphelins) 

COMP EMEA Committee on Orphan Medicinal Products http://www.emea.europa.eu/htms/gen 

eral/contacts/COMP/COMP.html 

CPA Dutch Committee for Pharmaceutical Aid 

DPBB Swedish Dental and Pharmaceutical Benefits Board http://www.tlv.se 

DRC Belgian Drug Reimbursement Commission 

(Commissie Tegemoetkoming Geneesmiddelen / 

Commission de Remboursement des Médicaments) 

DTC Diagnosis and Treatment Combinations (the 

Netherlands) 

EC European Commission http://ec.europa.eu/ 

EGAN European Genetic Alliance Network http://www.egan.eu/ 

EMEA European Medicines Agency http://www.emea.europa.eu/ 

EPAR European Public Assessment Report 

EU European Union http://europa.eu/ 

Eurordis European Organisation for Rare Diseases http://www.eurordis.org 

FDA US Food and Drug Administration http://www.fda.gov/ 

FPS Federal Public Service (former Belgian Ministry) 

GIS Groupe d’intérêt scientifique 

GVS Geneesmiddelenvergoedingssysteem (Dutch 

Medicines reimbursement system) 

HAS Haute Autorité de Santé (French High Health 

Authority) 

http://www.has-sante.fr 

HCIB Dutch Health Care Insurance Board (College voor 

Zorgverzekeringen) 

http://www.cvz.nl/ 

HTA Health technology assessment 

ICER Incremental cost-effectiveness ratio 

INAHTA International Network of Agencies for Health 

Technology Assessment 

www.inahta.org 

MA Marketing Authorisation 

MAH Marketing Authorisation Holder 

MD Medical Doctor 

MHRA British Medicines and Healthcare products 

Regulatory Agency 

http://www.mhra.gov.uk/ 

MS (European Union) Member States


NCG National Commissioning Group (body of the British 

NHS) 

http://www.ncg.nhs.uk/ 

NHS National Health Service 

NICE National Institute for Health and Clinical Excellence 

(UK) 

www.nice.org.uk 

NIHDI Belgian National Institute for Health and Disability 

Insurance (Rijksinstituut voor ziekte- en 

invaliditeitsverzekering / Institut National 

d’Assurance Maladie et d’Invalidité) 

www.NIHDI.be 

NORD National Organization for Rare Disorders (US) www.rarediseases.org 

OD Orphan drug 

ODD Orphan Drug Designation 

OOPD Office of Orphan Products Development of the FDA http://www.fda.gov/orphan/ 

ORPHANET The portal for rare diseases and orphan drugs www.orpha.net 

PA Protocol assistance (EMEA) http://ec.europa.eu/enterprise/pharma 

ceuticals/orphanmp/index.htm 

PCT Primary Care Trust (United Kingdom) 

PPRS British Pharmaceutical Price Regulation Scheme 

QALY Quality Adjusted Life Year 

RCT Randomized controlled trial 

RoI Return on Investment 

SA Scientific advice http://ec.europa.eu/enterprise/pharma 

ceuticals/orphanmp/index.htm 

SAWP Scientific Advice Working Party of the EMEA 

SMC Scottish Medicines Consortium http://www.scottishmedicines.org.uk 

SMR Service Medical Rendu (clinical added value) 

SSF Belgian Special Solidarity Funds (Bijzonder 

http://www.NIHDI.fgov.be/care/nl/info 

Solidariteitsfonds / Fonds Spécial de Solidarité ) s/solidarity/index.htm 

WGO Stuurgroep Weesgeneesmiddelen (Dutch Steering 

Committee on Orphan Drugs) 

www.weesgeneesmiddelen.nl 

WHO World Health Organisation www.who.org 

ZonMw Dutch Organisation for Health Research and 

Development 

http://www.zonmw.nl/


1 INTRODUCTION 

An rare disease is generally defined as a disease with a very low prevalence. Different 

operational definitions for rare diseases are used in legal documents and in literature. As 

such, the definition used in Europe differs from the one used in the United States. 

Rare diseases are often difficult to diagnose and specialized clinicians are most often 

scarce. Moreover, (drug) treatments for rare diseases are less likely to be produced by 

private companies because the market is too small and research and development costs 

for orphan products are usually too high to make the products profitable. Drugs used 

for the treatment of a rare disease are hereafter called orphan drugs. 

Both in the US and in the European Union incentives have been created to promote 

research and development on orphan drugs. Between 2000 and 2008 more than 590 

medicinal products received European orphan drug status. Almost 50 received 

marketing Authorisation in this period. About 30% of these were in the field of 

oncology and 27% in the field of endocrinology and metabolic disorders. 

It is estimated that there are currently between 5 000 and 8 000 different diseases that 

can be classified as rare. With less than 50 orphan drugs on the market at the end of 

2008, only a small part of the need for treatment of rare diseases is covered. 

Given the increasing number of orphan drugs and the high costs of orphan drugs, 

budgets spent to orphan drugs continue to increase. While in absolute numbers the 

total budget impact of orphan drugs might still be limited (about 2% of total hospital 

drug expenditures in 2009), their relative budget impact becomes steadily more 

important. 

As reimbursement policies with respect to orphan drugs differ between countries, 

access to orphan drugs also differs between countries. In the Belgian context, 

reimbursement of a product in Class I a requires evidence of the added therapeutic value 

of the product. However, due to the small number of patients with an rare disease, the 

clinical evidence base will often be weaker for orphan drug than for regular drugs. 

Economic evaluations of orphan drugs are often hampered by the limited evidence on 

clinical effectiveness for the drug. Moreover, using traditional approaches economic 

evaluations will usually find that orphan Drugs are not cost-effective because the cost 

for the additional health benefit the orphan drug treatment offers is usually high 

compared to many non)orphan treatments. 2 

The specific features of rare diseases and orphan drugs combined with the increasing 

number of rare diseases, makes them an issue of high priority for policy makers. On the 

one hand policy makers are faced with an increasing proportion of the health care 

budget being spent on orphan drugs, on the other hand they have to recognize the 

ethical and social dimension of rare disease treatment and deal with these under the 

constraint of not being able to expect the same level of clinical evidence for orphan 

drugs as for other drugs. 

a 

There are three added value classes in Belgium – the therapeutic value of a medicinal product is decided by 

the DRC and expressed in an added value class 

Class 1: medicinal products of which the therapeutic added value has been proven compared to existing 

therapeutic alternatives 

Class 2: medicinal products with no proven therapeutic added value compared to existing therapeutic 

alternatives 

Class 3: other medicinal products – categorized according to legislation 

Source: art. 5 Royal Decree 21/12/2001


1.1 OBJECTIVES OF THIS STUDY 

The main objectives of this study are: 

1. to provide an overview of the commonly used definitions for ‘rare diseases’ 

and ‘orphan drugs’ and describe the particularities of orphan drugs compared 

to regular drugs; 

2. to describe the regulatory process followed by an orphan drug, from orphan 

designation at the European level to reimbursement in Belgium and examine 

to what extent the information produced by the authorities responsible for 

orphan designation and Marketing Authorisation is directly useful for the drug 

reimbursement decision process; 

3. to compare the Belgian policy with regard to the reimbursement of orphan 

drugs with the procedures that exist in other countries for decision-making 

about the reimbursement of orphan drugs; 

4. to estimate the current budget impact of orphan drugs and make a prudent 

forecast of the expected budget impact in the years to come, and 

5. to formulate recommendations for policy makers concerning orphan drugs. 

Chapter 2 gives an overview of the different definitions for rare diseases and orphan 

drugs. Chapter 3 describes the European process from orphan designation to Marketing 

Authorisation and compares this with the process in the US. Chapter 4 compares the 

orphan drug reimbursement policies of 6 countries, including Belgium. Chapter 5 

describes the extent to which the information provided by the pharmaceutical 

companies to EMEA in order to obtain Marketing Authorisation and the public 

assessment report produced by EMEA corresponds with the information available to 

the Belgian drug reimbursement committee (DRC) at the time drug reimbursement is 

requested. Chapter 6 includes an analysis of the current budget impact of orphan drugs 

in Belgium and makes a prudent forecast of the expected budget impact in the coming 

years. Chapter 7 contains a discussion of the issues related to orphan drugs and chapter 

8 concludes the report with a number of recommendations for European and Belgian 

policy makers. We recommend to readers who want a quick insight to read the 

executive summary and chapter 7. 

1.2 GENERAL METHODOLOGY OF THE STUDY 

The methodology followed for this project can be summarised into seven activities. 

Activity 1: Desk research 

As a first activity, the contextual situation of the policy with regard to rare diseases and 

orphan drugs in Belgium was analysed against the European background. This included a 

collection and review of relevant documents and scholarly publications relating to the 

particularities of orphan drugs (such as market access, pricing, patient care, health 

technology assessments …). 

Activity 2: Policy description of the processes at EMEA and FDA 

The aim was to compare the Orphan Designation and Marketing Authorisation 

processes of the EMEA and FDA. Information was collected through desk research and 

interviews. 

Activity 3: Comparative analysis of the Belgian situation and of five other EU 

countries 

The third activity focussed on the Belgian reimbursement procedure: a description is 

provided of the criteria used for reimbursement of orphan drugs and of the differences 

of the decision process compared to other medicinal products. This work is based on 

qualitative research and interviews. The description of the Belgian situation is followed 

by an overview of the reimbursement procedure in France, Italy, the Netherlands, 

Sweden and the United Kingdom. Information for this activity was collected through 

desk research and a survey based on a qualitative questionnaire.


Activity 4: Budget impact analysis 

For all reimbursed orphan drugs in Belgium the budget impact was estimated based on 

the budget impact analysis presented by the companies in reimbursement request files 

and publicly available information (analysis of actual and expected budget impact over 

the years). Also forecasts and simulations of expected future budget impact of orphan 

drugs were made, using as a basis the average number of drugs getting marketing 

authorisation each year, the percentage of orphan drugs obtaining reimbursement in 

Belgium and the average cost per patient per year of orphan drugs. 

Activity 5: Critical assessment 

The critical assessment consisted of a ‘quick scan’ for all reimbursed orphan drugs in 

Belgium and a more in depth critical appraisal of eight cases (eight reimbursed and one 

negative case). The quick scan looked at the clinical and economic evidence provided in 

the context of the registration and reimbursement request files submitted to the 

NIHDI, whereas the in depth critical appraisal took into account the methodological 

standards of registration and reimbursement request files. The eight cases were 

selected according to a number of selection criteria (defined by the experts). 

Activity 6: Discussion of issues 

In Chapter 7 of this report eleven “issues” are presented which were identified through 

the study and which deserve attention at the policy-making level. This discussion offers 

some considerations which may serve as input for recommendations that follow from 

this study. 

In addition, personal interviews complemented the various other techniques used for 

the activities described above. These interviews took place with key actors involved in 

the process, both at the national and at the EU level, as well as with representatives of 

the various stakeholders, from COMP members, over EMEA or NIHDI to patient 

organisations and the pharmaceutical industry. 

Activity 7: Recommendations 

The recommendations were written by the KCE based on the results of the scientific 

review. 

Important comment for the reader: most figures mentioned in this report in relation to 

the number of orphan drugs are based on the situation as of the 31 st of December 

2008.


2 ORPHAN, RARE AND NEGLECTED 

DISEASES AND DRUGS: DEFINITIONS AND 

PARTICULARITIES 

2.1 INTRODUCTION 

Some conceptual confusion exists around the terms ‘rare diseases’ and ‘orphan drugs’. 

Different definitions of rare diseases and of orphan drugs are used in existing legislation 

of various countries and in literature on the subject. This chapter gives an overview of 

commonly used definitions. Orphan drugs are distinct from common drugs in terms of 

their development, Marketing Authorisation (MA), pricing, reimbursement and postmarketing 

follow-up. This chapter also discusses economic challenges of developing and 

marketing orphan drugs. 

2.2 METHODOLOGY 

A review of the international literature was carried out by searching the following 

electronic databases up to November 2008: PubMed, EMBASE, Bath Information and 

Data Services, Cochrane Library, EconLit, and Social Science and Citation Index. Search 

terms included ‘orphan diseases’, ‘rare diseases’, ‘neglected diseases’, ‘orphan drugs’, 

‘ultra-orphan drugs’, ‘research and development’, ‘Marketing Authorisation’, ‘pricing’, 

‘reimbursement’, ‘health technology assessment’, ‘economic evaluation’, ‘costeffectiveness’, 

‘post-marketing follow-up’, ‘risk sharing’, ‘patient registry’, ‘access’ and 

‘equity’. Additionally, the bibliography of included studies was checked for other 

relevant studies. Finally, information about regulation with respect to rare diseases and 

orphan drugs was gained from documents setting out international/national legislation. 

2.3 ORPHAN, RARE AND NEGLECTED DISEASES AND DRUGS 

The terms ‘orphan disease’ and ‘rare disease’ are frequently used interchangeably for a 

disease that affects only few persons in the population. However, according to some 

definitions orphan diseases comprise rare diseases as well as ‘neglected diseases’ 3 . The 

latter group consists of conditions that are prevalent in developing countries which are 

too poor to pay drug prices that render the new drug profitable for the patent-holding 

manufacturer. 4 This study will only focus on the group of rare diseases. 

When is a disease rare? The definitions that are used vary, but are usually expressed in 

prevalence figures. Table 1 gives an overview of the number of patients per 100 000 

individuals that countries apply to define a rare disease. 

According to the definition put forward by the European Union (EU), rare diseases are 

life-threatening or chronically debilitating conditions with a prevalence of 50 out of 

100,000 or less 5 . According to the World Health Organisation, a rare disease affects at 

most 65 out of every 100,000 individuals. 3 Australia, Japan and the United States have 

set prevalences of 11 6 , 40 7 and 66 8 per 100,000 individuals respectively for a given rare 

disease. The Swedish National Board of Health and Welfare defines rare diseases as 

disorders or injuries that result in extensive handicaps and that affect no more than 10 

per 100,000 individuals. 9


Table 1: Definitions of rare diseases based on prevalence 

Country Rare diseases 

Prevalence on 100,000 

Source 

US 66 a 

Orphan Drug Act 1983 

EU 50 Regulation EC n° 141/2000 

Japan 40 Orphan Drug Act 1993 

Australia 11 Orphan Drug Program 1997 

SE 10 Swedish National Board of Health and Welfare 

FR 50 Regulation EC n° 141/2000 

NL 50 Regulation EC n° 141/2000 

WHO 65 WHO 

a Based on a total US population of 304,354,998 on 16 June 2008. Source: US Census Bureau 

(http://www.census.gov/). In scholarly literature, the US prevalence rates for Orphan Designation 

expressed per 10,000 inhabitants vary from less than 6 to ‘about 10’ though. 

Within the group of rare diseases, some diseases are relatively more common than 

others. As a result, a distinction is sometimes made between rare diseases and ultrarare 

diseases. Ultra-rare diseases are generally defined as affecting less than 10,000 

individuals on a population of 300 million individuals. 10 In the UK, the National Institute 

for Health and Clinical Excellence (NICE) sets the prevalence of an ultra-rare disease at 

less than 2 per 100,000 individuals. 11 

Regardless of the country-specific definition, it is estimated that between 5,000 and 

8,000 distinct rare diseases exist today, 80% of which have identified genetic origins. 

Other rare diseases are the result of bacterial or viral infections and allergies, or are 

due to degenerative and proliferative causes. Together, rare diseases affect an important 

part of the population, estimated to be about 6% - 8% of the population of the 

European Union (EU), equivalent to 27-36 million people. 12 

2.4 ORPHAN DRUGS 

2.4.1 Background 

Due to their relatively low prevalence, rare diseases as a whole have traditionally been 

neglected by large parts of the scientific, medical and political communities. 13 With 

knowledge and awareness of the majority of rare diseases being scant or even absent, 

delay in diagnoses, lack of relevant information and difficulty in finding specialised 

physicians are common problems for affected patients. While many patients even 

remain completely undiagnosed, even when recognised, thousands of rare diseases 

cannot be treated because no therapies or drugs exist for them. This is primarily due to 

the fact that pharmaceutical companies are more interested in developing drugs for 

common disorders that affect millions of people than in the treatments for a few 

14 2005 

and because of a scientific deficit as research is less oriented towards rare diseases. As a 

consequence, sufferers from rare diseases are not only disadvantaged in terms of 

likeliness and timeliness of being diagnosed as such, but are on top of that experiencing 

unequal access to therapy and treatment in comparison to patients suffering from 

‘common’ diseases. 15 In the past decades, this unequitable situation gained recognition as 

a serious public health problem and it became clear that the development of drugs for 

rare diseases required special encouragement.


2.4.2 Definitions 

Orphan drugs are considered differently from other types of drugs by regulatory 

authorities. At EU level, discussions on orphan drugs started in the late nineties and led 

to the adoption of Regulation (EC) No 141/2000 of the European Parliament and of the 

Council of 16 December 1999, in which the justification for treating orphan drugs 

differently has been formulated as follows (preamble, paragraphs 1 and 2): 5 

1. (Whereas…) some conditions occur so infrequently that the cost of developing and 

bringing to the market a medicinal product to diagnose, prevent or treat the 

condition would not be recovered by the expected sales of the medicinal product; 

the pharmaceutical industry would be unwilling to develop the medicinal product 

under normal market conditions; these medicinal products are called ‘orphan’; 

2. (Whereas…) patients suffering from rare conditions should be entitled to the same 

quality of treatment as other patients; it is therefore necessary to stimulate the 

research, development and bringing to the market of appropriate medications by 

the pharmaceutical industry; 

Defining an ‘orphan drug’, Regulation (EC) No 141/2000 5 states (in Article 3.1) that: 

A medicinal product shall be designated as an orphan medicinal product if its sponsor can 

establish: 

(a) that it is intended for the diagnosis, prevention or treatment of a life-threatening or 

chronically debilitating condition affecting not more than five in 10 thousand persons in the 

Community when the application is made, or 

That it is intended for the diagnosis, prevention or treatment of a life-threatening, seriously 

debilitating or serious and chronic condition in the Community and that without incentives it is 

unlikely that the marketing of the medicinal product in the Community would generate 

sufficient return to justify the necessary investment; 

and 

(b) that there exists no satisfactory method of diagnosis, prevention or treatment of the 

condition in question that has been authorised in the Community or, if such method exists, that 

the medicinal product will be of significant benefit to those affected by that condition. 

In summary, the arguments put forward for considering orphan drugs differently than 

other drugs in the EU lie in the orphan drugs being economically not viable under 

normal market conditions and considerations of patient equity. 

2.4.3 Development 

In the EU, companies with an Orphan Designation for a medicinal product benefit from 

incentives such as: 16 

• protocol assistance (scientific advice during the product development 

phase); 

• direct access to the European Medicines Evaluation Agency (EMEA) 

Centralised Procedure with respect to registration; 

• Marketing Authorisation (10-year marketing exclusivity); 

• financial incentives (fee reduction b or exemptions, possible assistance with 

research and development) c ; 

• national incentives (detailed in an inventory of incentives made available by 

the European Commission 17 ). 

b Including a 100 % fee reduction for protocol assistance and 50% reduction for the application 

for Marketing Authorisation and 100% fee reduction for pre-authorisation inspections 

c In 2007, the funds made available by the Community for fee exemptions for orphan medicinal 

products amounted to € 6,000,000 (EMEA, 2007).


Article 9 of Regulation (EC) No 141/2000 requires Member States to communicate to 

the Commission detailed information concerning any measure they have enacted to 

support research into, and the development and availability of, orphan medicinal 

products or medicinal products that may be designated as such. The European 

Commission regularly publishes an inventory of such measures taken by the Member 

States according to article 9. d 

In the United States, incentives for the development of orphan medicinal products have 

been available since 1983. The United States’ Orphan Drug Act (ODA) 8 provides 

significant incentives for sponsors to develop and bring to the market drugs and 

biologicals, including vaccines and in vivo diagnostics to tackle rare diseases 13 . These 

benefits include expedited review by the US Food and Drug Administration (FDA) and 

thus shorter approval time, tax credits, seven years of marketing exclusivity and 

reductions of certain fees. Marketing exclusivity means that similar products have no 

access to the market for seven years. Furthermore, research grants are available to 

support clinical trials of orphan drugs. To qualify for incentives, drugs must receive the 

‘Orphan Designation’ from the FDA’s Office of Orphan Products Development 

(OOPD), and then go through the normal evaluation process for safety and efficacy. 18 

The ODA specifies, next to the prevalence criterion, that a drug is also considered as 

an orphan drug if scientists and economists at the Food and Drug Administration (FDA) 

determine that it will not be profitable for seven years after FDA approval. 

It should be noted that incentives for developing orphan drugs are important, but only 

constitute a means to an end. 2 The ultimate success of such incentives should be 

measured in terms of the increase in life expectancy and quality of life of patients with 

rare diseases. 

Chapter 3 deals in more detail with the comparison between the policies of the FDA 

and EMEA. 

2.4.4 Marketing Authorisation 

Figure 2.1 presents data on the number of Orphan Designations and Marketing 

Authorisations for orphan drugs, issued by the FDA and the EMEA from 2001 until 

2007. 

Since the EU developed a Regulation in 2000 to promote research and development on 

orphan drugs, about 270 medicinal products received European Orphan Designation 

and 22 received Marketing Authorisation from EMEA by 2005. These numbers 

increased to 570 with Orphan Designation and 47 that received MA by December 

2008. In the USA, more than 240 orphan drugs reached the American market in the 20 

years following the Orphan Drug Act became law, and over 900 experimental orphan 

drugs are in the research pipeline. 19 

The rapid increase in the number of Orphan Drug Designations and Marketing 

Authorisations give rise to general concerns regarding the budget impact these drugs 

have and will have on the existing health care systems and health care payers (both 

public and private) and the extent to which the current governance support to these 

drugs is economically sustainable 2 14 18 . 

Figure 2.1 gives an overview of the number of approved Orphan Designations and 

Marketing Authorisations by the FDA and the EMEA since 2001. The discrepancy 

between the numbers of FDA and EMEA is explained by the fact that the approvals in 

the USA started in 1984, increasing steadily over the years. 

d See inventories of 2001, 2002, 2005 17


160 

140 

120 

100 

80 

60 

40 

20 

0 

Figure 2.1 : Orphan Designation and Marketing Authorisation by the FDA 

and EMEA (2001-2007) 

2001 2002 2003 2004 2005 2006 2007 

2.4.5 Pricing 

OD: Orphan Designation; 

MA: Marketing Authorisation 

FDA - MA 

EMEA - MA 

FDA - OD 

EU - OD 

Prices of orphan drugs tend to be high. Both Genzyme and Shire, for example, are 

marketing some drugs in the EU with annual costs of € 200.000 to € 300.000 per 

patient (e.g. Aldurazyme® for mucopolysaccharidosis I and Fabrazyme® for Fabry 

disease). 20 There are several potential reasons for the high prices of orphan drugs. High 

prices may originate from marketing exclusivity, implying that no marketing 

authorization can be granted to a similar product with similar efficacy for the same 

therapeutic indication for a period of 10 years. The non-existence of an alternative 

treatment combined with the 10-year market exclusivity creates a monopoly for the 

company producing the orphan drug It should be noted, however, that marketing 

authorization can be granted to a clinically superior product, even if it is a similar 

product and market exclusivity can be reduced to 6 years if the criteria for orphan 

designation are no longer met. Also, the substantial costs of research and development 

have to be recouped from a small number of patients, thus resulting in high drug 

acquisition costs per patient. 13 However, orphan drugs do not always target a small 

number of patients. 

Certain products that were originally approved as orphan drugs, and as such benefited 

from special measures, later became top sellers either because the once rare condition 

they were intended to treat increased in frequency or because they proved also 

effective against more common disorderse.13 In these cases where profitability proves 

not to be a problem, public support is ex post deemed unjustified and critics in the US 

therefore urge for corrections to be made to the orphan drug legislation. In the EU, 

however, Article 8 of the Regulation provides for the possibility to reduce the 

marketing exclusivity to six years instead of ten years if, at the end of the fifth year, it is 

established that the product is sufficiently profitable. f Unsurprisingly, pharmaceutical 

companies lobby strongly against this article being put into practice and even argue that 

it should be eliminated completely. 21 Fact is also that there is no agreed definition of 

what is meant by “sufficiently profitable”. 

e Examples are Glivec® and Sutent®. 

f Situation on July 9th, 2009


2.4.6 Health technology assessment and reimbursement 

In a context of spiralling health care costs and limited resources, public policy makers 

and health care payers are increasingly using health technology assessments, including 

economic evaluation and budget impact analysis, to inform reimbursement decisions. 

However, the use of health technology assessment in the field of orphan drugs for 

reimbursement purposes is challenging for a number of reasons as described below. 

The reimbursement of orphan drugs is not regulated at EU level, but is a national 

responsibility of Member States. Once products have received Marketing Authorisation 

from EMEA, there are important differences to be noted among the EU Member States 

in terms of availability of these products on these markets, in the delays of availability 

between the Member States and in the prices of the same orphan medicine between the 

Member States. 19 Based on these observations, patient groups like the European 

Organisation for Rare Diseases (Eurordis) and the European Genetic Alliance Network 

(EGAN) are arguing for the elimination of regional and national differences in 

distribution, taxation and reimbursement policies, factors which combined explain the 

differences of up to 70% for the annual cost per patient of a given orphan medicine 

between various EU countries. 13 

Given their high price for an often modest health benefit orphan drugs are unlikely to 

be cost-effective, at least if the cost-effectiveness of an intervention is judged based on 

its cost per quality adjusted life year (QALY) gained in its neo-classical welfarist sense, 

and this cost-per-QALY is compared to a fixed threshold value. 22 If reimbursement 

decisions are primarily based on cost-effectiveness considerations and budget impact, 

orphan drugs will tend to fail these criteria. However, most often additional criteria that 

are not included in the traditional cost-per-QALY measure, are used to inform 

reimbursement decisions. 22 For instance, the Pharmaceutical Benefits Advisory 

Committee of Australia also takes account of: the seriousness of the health condition; 

the availability of other therapies to treat the disease; and the cost to the patient if the 

drug is not reimbursed. 23 These criteria are particularly relevant to orphan drugs, which 

tend to target serious health conditions, make up the single strategy to treat a disease, 

and have a huge impact on patients’ health care expenditures if they would have to pay 

for the drugs themselves. 

With a view to assessing the effectiveness of an orphan drug, it is difficult to enrol a 

sufficient number of patients in clinical trials. As these diseases affect only few patients 

at a time, it is in many cases hardly possible to gather enough patients to achieve 

sufficient statistical power to demonstrate clinical effectiveness of a given treatment. 24 

Moreover, also because the disorders are rare, few medical centres will have sufficient 

long-term experience with affected patients to be able to describe the natural history of 

the diseases. Other authors also point out that in many rare disorders there is a lack of 

knowledge on disease processes, on the precise influence of genetics, on prevalence 

figures, and on how to conduct clinical trials. 19 These authors emphasise that increased 

efforts to address these issues are urgently needed at the European Community level. 

One of the authors therefore suggests to modify the review process for rare disease 

therapies: allow greater use of rational surrogate outcome measures if clinical efficacy 

data are incomplete, but require from industry to support a process of continuing 

review of clinical outcomes. A central component of the process would therefore be a 

commitment to ongoing evaluation of patients through registries designed to collect 

clinical information on patients receiving the new therapy. 24 

A patient registry would allow regulatory authorities to follow up and evaluate the 

uncertainties surrounding longer-term effectiveness and cost-effectiveness of an orphan 

drug in the relevant population. 25 Such an approach would support the decision-making 

process and allow more timely access to orphan drugs for patients. Also, data on (cost-) 

effectiveness from patient registries can be used by researchers and clinicians to inform 

clinical practice and prescribing guidelines. Such patient registries could even be 

integrated with national pharmacovigilance systems providing information about adverse 

events associated with orphan drugs. However, it should be noted that there are 

challenges involved in setting up a patient registry and analysing registry data. They 

could also be different if set-up independently or by industry.


The patient registry may be biased as the patient aetiology and disease severity change 

over time. Also, as patient registries collect data on an orphan drug, but not on 

alternative treatments, they only provide partial information to calculate the 

incremental cost-effectiveness of the orphan drug relative to an alternative treatment. 

Furthermore, new treatment strategies may become available during the period 

covered by the registry. Therefore, patient registries need to be set up and developed 

in a flexible way to be able to account for changes in patient population and treatment 

strategies over their lifetime. 

For instance, the MPSI Registry is an ongoing, observational database that tracks natural 

history and outcomes of patients with MPSI g . Initiated worldwide in April 2003, data 

from over 718 patients with MPSI have been collected from physicians in over 30 

countries as of May 2008. 

Reimbursement may not only depend on the value for money of an orphan drug at the 

time of the reimbursement application, but also on its value after a number of years 

following the admission to the reimbursement system. Under such a system of 

conditional reimbursement, pharmaceutical companies need to explore setting up 

patient registries to inform the post-launch cost-effectiveness of an orphan drug. 

Reimbursement authorities may also wish to consider a risk-sharing scheme between 

drug sponsor and government based on a registry system whereby survival outcomes 

are linked to future drug prices. 25 Risk-sharing agreements allow authorities to balance 

the uncertainty of long-term cost-effectiveness with the need to provide equitable 

access to potentially effective but expensive orphan drugs. Such agreements may incite 

the drug sponsor to promote responsible prescribing of orphan drugs; provide a 

guarantee on health outcomes with a view to attaining predictable health gains for a 

given drug expenditure; and share the budgetary risks between authorities and the drug 

sponsor. However, risk-sharing agreements entail that structures are set in place that 

safeguard the objective of computing the post-marketing cost-effectiveness of orphan 

drugs based on a representative and unbiased sample. Also, risk-sharing agreements 

should be flexible to reflect the introduction of new treatment strategies over the 

monitoring period of the agreement. Nevertheless, Owen et al. conclude that such 

schemes may allow to balance the uncertainty of long-term cost-effectiveness 

with the public demand for equitable and timely access to new orphan drugs, 

on the condition that some issues like governance, privacy, ethics review, timely and 

accurate data, related to such registry system are adequately addressed. 25 

2.5 CONCLUSIONS 

A wide variety of definitions of rare diseases and of orphan drugs are used in the 

legislation of various countries. Also, a number of challenges exist with respect to the 

development, Marketing Authorisation, pricing, reimbursement and post-marketing 

follow-up of orphan drugs. As a result, the need is expressed for more transnational 

cooperation and the building of an active and international community able to act and 

address the economic and intellectual efforts towards solving the most pressing 

difficulties as described above. 19 

g http://www.lsdregistry.net/mpsiregistry/


Key points 

• Different definitions of rare diseases and of orphan drugs are used in the 

existing legislation of various countries and in literature. For the purpose of 

the present study, EU official definitions for rare diseases and for orphan 

drugs are adopted. 

• Rare diseases are life-threatening or chronically debilitating conditions with 

a prevalence of 50 out of 100 000 or less. 

• Due to their relatively low prevalence, rare diseases have traditionally been 

neglected by large parts of the scientific, medical and political communities. 

As a result, patients suffering from rare diseases may experience unequal 

access to treatment in comparison to patients suffering from ‘common’ 

diseases. 

• In the EU, orphan drugs are considered differently from other drugs for 

reasons of absence of economical viability under normal market conditions 

and because of considerations of patient equity. With a view to supporting 

the development of orphan drugs, the EU has put in place a number of 

incentives. 

• However, the resulting rapid increase in the number of orphan drugs 

obtaining designations has given rise to concerns about the overall potential 

budget impacts on health care systems and health care payers. 

• Reimbursement decisions for pharmaceutical products are also based on 

cost-effectiveness considerations, but orphan drugs will tend to fail these 

criteria because the cost of orphan drug treatments is usually high for the 

benefits they offer compared to many non-rare disease treatments. 

Additional criteria, such as the seriousness of the disease and the availability 

of other therapies, can become more important in reimbursement decisions 

of orphan drugs but are generally not incorporated in a standard economic 

evaluation.


3 POLICY DESCRIPTION 


The process from Orphan Designation to Marketing Authorisation is governed by the 

European Medicines Agency (EMEA) in Europe and the Food and Drug Administration 

(FDA) in the United States. This chapter compares the EMEA and FDA procedures with 

a view to identifying differences and discussing the implications of different approaches 

to Orphan Designation and Marketing Authorisation. 

3.2 EMEA PROCESS: FROM ORPHAN DESIGNATION TO 

MARKETING AUTHORISATION 

3.2.1 Presentation of EMEA 

“The European Medicines Agency is a decentralised body of the European Union with 

headquarters in London. Its main responsibility is the protection and promotion of public and 

animal health, through the evaluation and supervision of medicines for human and veterinary 

use”. 26 

Until recently, the possibility also existed to obtain a Marketing Authorisation by a 

mutual recognition procedure. Since 2005, only the central procedure at EMEA can be 

used to register a product and obtain Marketing Authorisation. 

The two main actors in the orphan drug procedures are the Committee for Orphan 

Medicinal Products (COMP) and the Committee for Human Medicinal Products 

(CHMP). 

The COMP is EMEA’s committee responsible for examining the applications for Orphan 

Designation: the European Commission (EC) will approve or reject an application based 

on the COMP’s opinion. The COMP has two main activities: 

Scientific evaluation Public Health Activities 

• To examine applications for Orphan 

Drug Designations 

• Protocol assistance 

• Re-evaluation of significant benefit 

during Marketing Authorisation 

registration 

• Post-Marketing Authorisation review 

every 5 years 

• Advise the EC on the establishment and 

development of a policy on orphan 

medicinal products for the EU 

• Assist the EC in liaising internationally on 

matters relating to orphan medicinal 

products, and in liaising with patient support 

groups 

• Assist the EC in drawing up detailed 

guidelines 

• EU expert network and visibility 

The COMP is composed of: 

• one chairperson and one vice-chairperson; 

• one member per Member State (27 Member States in 2008); 

• three members representing patient organisations (nominated by the EC); 

• three members recommended by EMEA (nominated by the EC); 

• one non-voting member per EEA-EFTA h state (Norway and Iceland in 

2008). 

The members are appointed by their country, while the chairperson and vicechairperson 

are elected by and from the COMP members on basis of a brief resume of 

the candidates and with an absolute majority i . 

h 

EEA-EFTA: European Economic Area – European Free Trade Association 

i 

An absolute majority is obtained when more than 50% of the members has voted in favour of the 

candidate.


All the members are appointed for a period of three years with possibility of renewal 

(the same applies for the CHMP members). 

The CHMP is the committee responsible for examining the applications for Marketing 

Authorisation for all medicinal products, but also for the post-authorisation follow-up. 

The CHMP is composed of: 

• a chairman, elected by and from the CHMP members; 

• one member (and an alternate) per Member State (27 Member States in 

2008); 

• one member (and an alternate) per EEA-EFTA state (Norway and Iceland 

in 2008); 

• up to five co-opted members (experts recruited to gain additional 

expertise in a particular scientific area). 

The European Orphan Drug policy has been regulated by Regulation (EC) No 141/2000 5 

on orphan medicinal products. There are two steps to be taken before an orphan drug 

is admitted on the market: 

• Step 1: Orphan Designation: a medicinal product receives the orphan 

status – linked to incentives. 

• Step 2: Marketing Authorisation: is the marketing approval of a drug for 

an orphan condition. It becomes orphan drug and receives market 

exclusivity. 

3.2.2 Applying for Orphan Designation 

3.2.2.1 Conditions to be fulfilled 

A medicinal product can obtain the designation of orphan medicinal product if it 

provides treatment for a rare disease. In order for a pharmaceutical firm to be able to 

apply for an Orphan Designation, two conditions must be fulfilled (see art. 3 of 

Regulation (EC) no 141/2000): 

• the medicinal product is intended for the diagnosis, prevention or 

treatment of a life-threatening or chronically debilitating condition that 

either affects less than 5 in 10,000 persons of the Community; or that 

without incentives it is unlikely that the marketing of the medicinal 

product would generate sufficient return to justify the expenditure; 

• a satisfactory method for diagnosis, prevention or treatment of the 

condition does not exist. 

The COMP will essentially take decisions at two levels corresponding to the two 

conditions defined in the above-mentioned article of the Regulation: 

Level 1: Prevalence or Insufficient return 

Level 2: Absence of solution or Significant benefit 

Other criteria to obtain Orphan Designation are: the “medical plausibility” of the 

condition and sub-setting. 

In case of insufficient return it is unlikely that the expected return would justify the 

required investment and so it is unlikely that the sponsor would be prepared to make 

the investment. 27 

Absence of solution means that there is no alternative treatment available, while 

significant benefit 28 means that the drug has a clinically relevant advantage or major 

contribution to patient care compared to existing satisfactory methods for diagnosis, 

prevention or treatment. The significant benefit can be related to: 

• improved efficacy and / or safety; 

• ease of self administration: leading to a major contributions to patient 

care;


• new mechanism of action: of which the efficacy will have to be 

demonstrated. This new mechanism opens possibilities for drug 

combination and can be designated as a therapeutic alternative 29 ; 

• reduced availability of the base materials; 

• reduced availability of the product in the EU Member States (not possible 

after centralised registration). 

Significant benefit must be confirmed by the sponsors during registration application, 

and questions about it must have been answered during protocol assistance. Appraisal 

of the criterion thus occurs at three times: 1. first application at COMP for Orphan 

Designation; 2. protocol assistance prior to Marketing Authorisation; 3. MA registration 

application (compulsory). The COMP will assess if the significant benefit can be 

confirmed by available data and/or evidence supplied by the applicant (at the moment 

the CHMP takes its decision). 

A subset 28 is a separated part of a (frequently occurring) disease, having an own 

pharmacotherapeutic treatment and without this subset the drug would have no effect 

in the remaining population. Sub-setting is rarely accepted. Are not accepted: 

• different levels of seriousness or localisation of a disease; 

• the subset is based on a (post-hoc) analysis of the study of a product that 

should function for the whole group. 

Sub-setting can lead to so-called “salami-slicing”: this is creating artificial subsets of a 

non-orphan condition, by basing the prevalence criterion on an unreal subpopulation. 

The aim is to obtain market exclusivity, a decrease of the costs and obligations linked to 

the registration demand, and an increase of the exclusivity through new subpopulations 

(also known as the “evergreening tactic”). 

Medically plausible subsets are based on the real disease process; the seriousness of 

the condition; the characteristics of the drug; the working mechanism and the unique 

characteristics of the patient population. In order for a subset to be accepted, the 

sponsor must justify the medical plausibility why the drug should be restricted to the 

sub-set. 30 

In practice, of the 541 molecules or products that received the designation, 540 

obtained it based on the criterion “prevalence”, and one product obtained designation 

based on the criterion of “return on investment” j (a second application was withdrawn 

by the sponsor 30 ). 

3.2.2.2 Orphan Designation Procedure 

The application dossier must include: 

• the name or corporate name and permanent address of the sponsor; 

• active ingredients of the medicinal product; 

• proposed therapeutic indication; 

• a justification that the two conditions mentioned in article 3 are met; 

• and a description of the stage of development, including the therapeutic 

indications expected. 

The Orphan Designation procedure is described in figure 3.1. This is the centralised 

procedure which is compulsory for orphan drugs since 2005. k 

The COMP will adopt its opinion with a consensus, and if impossible with a two-thirds 

majority. The European Commission may take a draft decision that is different of the 

COMP’s opinion, but this decision must be approved by the Council of the EU (See art. 

73 of Regulation (EC) 2309/93) 31 . 

j This orphan drug designation was obtained for the treatment of neglected disease (as opposed to rare 

disease). 

k For non-orphan drugs, it is also possible to proceed through the mutual recognition procedure and the 

decentralised or national procedure.


90 days 

30 days 

Following the publication of the orphan product in the Community Register of Orphan 

Medicinal Products, the sponsor will annually submit to the EMEA a report on the state 

of development of the product (See art. 5§10 of Regulation (EC) 141/2000) 5 . 

Figure 3.1 : Orphan Designation Procedure 

Sponsor submits application form to the EMEA 

anytime during the development process of the 

product 

- Appointment of 2 coordinators: 

COMP member + EMEA staff member 

- EMEA verifies validity 

- The EMEA coordinator prepares a 

summary report of the application for 

the COMP members start of the 

evaluation time-table 

COMP must give an opinion within 90 days of 

reception based on the summary report and its 

members’ comments 

European Commission takes a decision based on 

the opinion within 30 days and informs sponsor, 

EMEA and Member States 

The designated orphan medicinal product is 

registered in the Community Register of Orphan 

Medicinal Products 

Post-designation: the sponsor submits an annual 

report on the state of development of the 

product (this is an administrative procedure – no 

sanction) 

Pre-submission meeting 

is possible 

Sponsor may appeal 

within 90 days following 

the opinion 

In order to encourage research and development of orphan medicinal products, the 

Orphan Regulation incorporates five incentives. The first incentive can take place 

before or after applying for Orphan Designation: thanks to the protocol assistance (1), 

the company may request scientific advice of the EMEA on the conduct of various tests 

and trials necessary to demonstrate the quality, safety and efficacy of the medicinal 

product. Once the medicinal product has been given the status of orphan, it has direct 

access to the centralised procedure (2) for the application for Marketing Authorisation. 

If this latter is granted, the orphan medicinal product receives a 10-year market 

exclusivity (3) meaning that similar products have no access to the market (unless they 

have a significant benefit or are superior). 

Orphan medicinal products will also benefit from fee reductions (4) for centralised 

applications and obtain grants within the framework of EU-funded research (5) as well 

as priority access to EU research programs.


The market exclusivity can be brought back to six years if the sponsor having applied 

first for a designation gives its consent that a second sponsor can obtain the same 

designation; there is a lack of drug supply; or if the new drug is safer, more effective of 

clinically superior. 29 The market exclusivity may also be withdrawn after six years if the 

medicinal product no longer meets the two conditions necessary to obtain Orphan 

Drug Designation. 

In 2007, 4.89 million € of fee reductions was granted through the fee reduction 

mechanisms (applicable after Orphan Drug Designation is obtained). 

Figure 3.2 : Overview of incentives and other compensations 

Incentives: 

1. 10 years market exclusivity 

2. Protocol and scientific assistance 

3. Financial incentives on a national basis 

4. Direct access to centralised procedure 

5. Access to EU-funded research 

Other compensations: 

1. The fee reductions can be the following: 16 

o 100% reduction for protocol assistance and follow-up; 

o 100% reduction for pre-authorisation inspections; 

o 50% reduction for applications for Marketing Authorisation; 

o 50% reduction for post-authorisation activities, including annual fees, 

in the first year after granting of a Marketing Authorisation. 

2. 12-year market exclusivity if paediatric orphan drug (Paediatric development 

since 1/7/2008) 

3. Guidance for clinical trials in small populations 32 in order to increase the 

efficiency of the design and the analysis 

Figure 3.3 : Use of EU special funding contribution for orphan medicines 

(2007) 

68% 

5% 3% 

24% 

Marketing Authorisation 

Protocol assistance 

Inspections 

Post-authorisation 

Source: EMEA. Annual report of the European Medicines Agency 2007. Doc. ref.: 

EMEA/MB/17464/2008 13 May 2008. Available from 

[Last accessed: 

10/12/2008].


The table in figure 3.4 gives an overview of the yearly number of applications for 

Orphan Designation since 2000. Of 896 initial applications 226 have been withdrawn. 

92% of the remaining applications have received a positive COMP opinion and 89% a 

final designation. 

Figure 3.4 : Orphan Designation between 2000 and November 2008 

Year Applications 

submitted 

Positieve 

COMP 

Opinions 

Applications 

withdrawn 

Final negative 

COMP Opinions 

Designations 

granted by 

the 

Commission 

2008 119 86 31 1 73 

2007 125 97 19 1 98 

2006 104 81 20 2 80 

2005 118 88 30 0 88 

2004 108 75 22 4 72 

2003 87 54 41 1 55 

2002 80 43 30 3 49 

2001 83 64 27 1 64 

2000 72 26 6 0 14 

Total 896 614 226 13 593 

Source: Committee for Orphan Medicinal Products. January 2009 Plenary Meeting, Monthly 

Report. EMEA. Doc. Ref.: EMEA/COMP/694107/2008. 7 January 2009. Available from 

[Last accessed: 10/3/2009]. 

3.2.3 Applying for Marketing Authorisation 

Before applying for a Marketing Authorisation, the pharmaceutical company can request 

scientific advice and protocol assistance from the Scientific Advice Working Party 

(SAWP), part of the CHMP. The advice is given for the conduct of tests and trials in 

order to demonstrate the quality, safety and efficacy of the medicinal product (Art. 6 

Regulation (EC) No. 141/2000) 5 , while the assistance provides guidance and verifies the 

criteria. 

Figure 3.5 : Scientific-advice and protocol-assistance requests received, 2005-2007 

2007 

2006 

2005 

58 

58 

68 

0 50 100 150 200 250 

Scientific-advice and follow-up requests Protocol-assistance and follow-up requests 

Source: EMEA. Annual report of the European Medicines Agency 2007. Doc. ref.: 

EMEA/MB/17464/2008 13 May 2008. Available from 


10/12/2008]. 

136 

201 

213


l CHMP/EWP/83561/2005 

The SAWP’s tasks are to: 33 

• provide the CHMP an integrated view about the quality, pre-clinical and 

clinical safety including pharmacovigilance and risk/minimisation aspects, 

and efficacy, relating to the development of orphan medicinal products; 

• provide protocol assistance to the CHMP as regards the demonstration of 

significant benefit relating to orphan medicinal products; 

• provide advice on applying for a conditional MA or MA under exceptional 

circumstances; 

• provide advice on the design of trials to assess safety and efficacy in a new 

indication expected to bring significant clinical benefit compared to 

existing therapies; 

• pay special attention to development and methodology issues of products 

intended for small populations. 

In 2006, the CHMP developed guidelines on clinical trials in small populations. l They 

came into effect on February 1st, 2007. The guidelines acknowledge that in 

circumstances where only few patients are affected by a disease, a trial enrolling several 

hundred patients may not be practical or possible. Meanwhile it is stated that “most 

orphan drugs and paediatric indications submitted for regulatory approval are based on 

randomised controlled trials that follow generally accepted rules and guidance.” The 

guidelines state that “deviation from such standards is, therefore, uncommon and 

should only be considered when completely unavoidable and would need to be 

justified.” 

After having received the Orphan Designation the sponsor can apply for a Marketing 

Authorisation (the procedure is presented in figure 3.6). This can only be done through 

the centralised procedure at the EMEA. For normal drugs, a national procedure exists 

as well. Within 210 days the CHMP gives a final opinion that is transmitted to the 

European Commission who will take the concluding decision. 

The MA procedure consists of three steps: 

1. Pre-submission 

2. Primary evaluation 

3. Secondary evaluation 

An accelerated review of the medicinal product is possible when decided by the CHMP. 

The product must fulfil three conditions: 

• the condition is life threatening or serious; 

• there is no effective therapeutic alternative; 

• and the drug is expected to have a high therapeutic benefit. 34 

1. Pre-submission phase 

The sponsor (named hereafter ‘applicant’) sends a letter of intent to the CHMP 

together with a fee for the examination. The CHMP examines the validity of the 

application: 

• examination of the submitted particulars and documents; 

• it may request that the medicinal product be tested; 

• and it may request that the applicant supplements the particulars 

accompanying the application within a specific time period. 

A rapporteur and a co-rapporteur will be appointed to evaluate the MA application. The 

appointment is based on the best available expertise. Each rapporteur will have an 

assessment team composed of assessors of the national authorities and can appoint 

experts if necessary.


Within EMEA, a product team leader and his/her team are appointed in order to 

prepare the documents of the CHMP and to liaise between the applicant and the 

CHMP. 

2. Primary evaluation 

On Day 80 of the MA process, the two rapporteurs each produce an assessment report 

in which is given a detailed overview of the quality, clinical and non-clinical data given in 

the submission file, and possibly a proposal of list of questions. 

The assessment reports are sent to the CHMP members for comments and to the 

applicant for information. The reports are also peer reviewed by a CHMP member and 

by the EMEA product team leader in order to see if they are consistent and if there is a 

sufficient level of detail. 

A list of questions is produced by the CHMP and sent to the applicant on Day 120. 

3. Secondary evaluation 

A Joint Assessment Report is produced by the rapporteurs following the reception of 

the responses of the applicant. The report is sent to the CHMP on Day 150 for 

comments resulting in a list of outstanding issues to be sent to the applicant on Day 

180. Following the reception of the applicant’s responses, a second joint assessment 

report is sent to the CHMP members. 

The different assessment reports and the lists of questions serve as a basis for the 

redaction of the CHMP assessment report which underpins the CHMP opinion. The 

CHMP opinion is based on the examination of the risk-benefit balance of the medicinal 

product; this is an evaluation of the positive therapeutic effects of the medicinal product 

in relation to the following risks: 

• any risk related to the quality, safety or efficacy of the medicinal product 

as regards patients' health or public health; 

• any risk of undesirable effects on the environment. 

The CHMP issues a positive or negative opinion based on the risk-benefit ratio. There is 

no comparison with other drugs. 

The opinion is sent to the European Commission who takes the final decision. Refusal 

reasons are either that the quality, safety or efficacy of the product is not 

demonstrated; or that particulars or documents are incorrect. If the EC decision is 

different from the CHMP’s opinion, then it will be sent to the Member States. The 

applicant is notified in both cases. 

The CHMP assessment report also serves as a basis for the redaction of the European 

Public Assessment Report (EPAR) which is published on EMEA’s website and available 

for the public.



REDACTION EPAR 

Figure 3.6 : Marketing Authorisation Procedure 

Day 1 Start procedure 

Day 80 Assessment report of rapporteur and corapporteur 

sent to CHMP 

Day 120 List of questions of CHMP sent to applicant 

Day 150 Joint assessment report from both 

rapporteurs based on applicants’ answers 

Day 180 List of outstanding issues 

Day 181 Second joint report of rapporteurs 

Day 210 Adoption of CHMP assessment report and 

opinion 

To applicant: is there any information that should be 

deleted because commercial sensitive? 

Agreement on content 

EPAR DRAFT I (assessment report and EPAR Summary 

(positive opinion) / Q&A (negative opinion) 

Comments CHMP members 

Comments CHMP members 

If comments from members CHMP 

EPAR DRAFT II 

Adoption EPAR DRAFT I/II by CHMP Finalisation 

EPAR 

European Commission’s 

decision


The MA procedure is the same for all human medicinal products, orphan and nonorphan 

drugs: EMEA evaluates the quality, safety and efficacy of the drug. The only 

differences for orphan drugs are: 

1. the involvement of the COMP who will review the significant benefit 

criterion: are the criteria on which the decision for the Orphan Designation 

were taken still valid? This takes place when the CHMP prepares its opinion. 

2. the existence of guidelines for clinical trials in small populations, which are 

used as a basis to assess the clinical evidence provided. 

The MA is granted if: 

1. The medicinal product contains a new active substance which was not 

authorised in the Community; or 

2. The applicant shows that the medicinal product constitutes a significant 

therapeutic, scientific or technical innovation or that the granting of 

authorisation is in the interests of patients at Community Level. 

A medicinal product cannot receive a MA for an orphan indication and for a nonorphan 

indication. In case of conflict, the orphan indication will have to be disposed of 

or the medicinal product will have to request MA under a different name. For example, 

the drugs Viagra® and Revatio® have the same composition, but the first is reimbursed 

for a non-orphan indication, the second for an orphan indication (Pulmonary Arterial 

Hypertension). 

The MA is valid for five years and can be renewed for five-year periods after review 

(Art. 13 Regulation (EC) No. 2309/93). 31 

There is a possible access to accelerated review to MA if duly substantiated by the 

sponsor (150 days instead of 210 days). The review can be requested for medicinal 

products for human use which are of major interest from the point of view of public 

health and of therapeutic innovation. 

In 2008, fourteen MA applications have been submitted for orphan medicinal products. 

Seven have received a positive opinion and two a negative opinion. Six sponsors have 

withdrawn their application prior to the opinion. The European Commission has 

granted five MA. 35 

Figure 3.7 : Overview of Marketing Authorisations for Orphan Drugs (2001- 

2008) 

Number of approved MA per year 

14 

12 

10 

8 

6 

4 

2 

0 

2001 2002 2003 2004 2005 2006 2007 2008 

Number of approved MA per year Total number of MA 

Source: DG Enterprise EC. Register of designated Orphan Medicinal Products. 

. 11/3/2009. 

60 

50 

40 

30 

20 

10 

0 

Total number of MA per year


Figure 3.8 : Total of Orphan Drugs per therapeutic area (December 2008) 

Cardiovascular 

& respiratory 

14% 

Nervous 

system 

8% 

Haematology 

16% 

Other 

6% 

Oncology 

29% 

Endocrinology / 

metabolism 

27% 

Source: EMEA. List of orphan-designated authorised medicines 6/11/2008. Available from 


There are three types of MA: the normal MA, the conditional MA and the MA under 

exceptional circumstances. 

The normal MA is valid for five years and may be renewed on the basis of a reevaluation 

by EMEA of the risk-benefit balance. After this renewal, the MA will be valid 

for an unlimited period of time unless decided otherwise. The medicinal product must 

be placed on the market within three years otherwise the Authorisation is no longer 

valid. The same applies when the product has been unavailable for three consecutive 

years. 

The conditional MA is regulated by Regulation (EC) 726/2004. This second type of 

MA is granted on the basis of less complete clinical data. Conditions are that the riskbenefit 

balance is positive, there is a benefit to public health of immediate market 

availability (outweighing the risks inherent to the fact that additional data are still 

required) and that unmet medical needs will be fulfilled. The conditional MA is valid for 

one year and can be renewed. Once the missing data have been completed, the drug 

will receive a normal MA. 

The MA under exceptional circumstances is given when comprehensive data 

cannot be provided because of the small study population. This MA will be reviewed 

annually to reassess the risk-benefit balance based on follow-up studies including 

pharmacovigilance studies. The orphan drugs Tracleer® and Fabrazyme® have received 

normal MA after fulfilling the data. 

As of December 2008, there was one orphan drug with a conditional MA and sixteen 

with an exceptional MA. This means that five out of eight orphan drugs are authorised 

under exceptional circumstances. Following figure shows that the exceptional status is 

given at least once yearly and is not something which was mostly used in the early years 

of the legislation.


Figure 3.9: Overview of Exceptional Marketing Authorisations (2001-2008) 

5 

4 

3 

2 

1 

0 

2001 2002 2003 2004 2005 2006 2007 2008 

Source: DG Enterprise EC. Register of designated Orphan Medicinal Products. 

. 11/3/2009. 

3.2.4 Compassionate use 

Compassionate use is possible for new medicinal products to be approved through the 

centralised procedure of EMEA: therefore three conditions states in art. 83 of 

Regulation (EC) No 726/2004 36 must be fulfilled: 

• The medicinal product is to be made available to “patients with a 

chronically or seriously debilitating disease, or a life threatening disease, 

and who cannot be treated satisfactorily by an authorised medicinal 

product” in the EU, 

• The compassionate use programme is intended for a “group of patients”, 

• The medicinal product is either “the subject of an application for a 

centralised Marketing Authorisation in accordance with Article 6 of 

Regulation (EC) No 726/2004 or is undergoing clinical trials” in the EU or 

elsewhere. 

The aim of the compassionate use programme is to facilitate access for patients to a 

new medicinal product. 

There are also compassionate use programmes at a national level which differ between 

Member States. Some of them are addressed in the next chapter. 

3.3 FDA PROCESS: FROM ORPHAN DESIGNATION TO 


3.3.1 Presentation of the FDA 

The Orphan Drug Act signed in 1983 was the first orphan drug legislation adopted in 

the world. It defines an orphan drug as a drug that is intended to treat a condition 

affecting fewer than 200,000 persons in the United States, or which will not be 

profitable within 7 years following approval by the U.S. Food & Drug Administration 

(FDA). 37 

The legislation regulating the Orphan Drugs Policy in the United States can be found in 

the Code of Federal Regulations (CFR), Title 21, Part 316: Orphan Drugs. 38 The 

authority in charge is the Office of Orphan Products Development (OOPD) of the 

FDA. The OOPD’s primary objective is to promote the development of products that 

demonstrate promise of the diagnosis and/or treatment of rare diseases or conditions. 39 

In order to obtain marketing approval, a drug first has to obtain Orphan Drug 

Designation. Up to April 2007, over 1,400 orphan products have been designated and a 

little more than 300 orphan products (of which 85% are drugs) have been approved 

since 1983. 37


3.3.2 Orphan Drug Designation 

A sponsor can apply for the designation at the OOPD at anytime during the 

development process. 

The product has to satisfy one of the following criteria: 8 

1. prevalence criterion: less than 200,000 persons in the US suffer from the 

disease; or 

2. return on investment: even if there are more than 200,000 persons in the US 

suffer from the disease, there is no expectation that the costs of research and 

developing of the drug for the indication can be recovered by sales of the 

drug in the US. 

The drug can also obtain the Orphan Designation if scientists and economists of the 

FDA determine that the drug will not be profitable for seven years after FDA approval, 

regardless of the number of patients affected. 

In May 2008 there were 325 designated orphan drugs with a marketing approval of 

which three were approved based on the ‘return on investment’-criterion. 40 

The Orphan Drug Designation will not be affected by a change in prevalence of the 

disease. 41 

In order to apply for an Orphan Drug Designation, the sponsor must submit following 

elements to the OOPD: 42 

• a statement requesting Orphan Drug Designation for a rare disease or 

condition; 

• a description of the rare disease or condition, the proposed indication or 

indications for use of the drug, and the reasons why such therapy is 

needed; 

• a description of the drug and a discussion of the scientific rationale for the 

use of the drug for the rare disease or condition; 

• if an alternative already exists, an explanation why the proposed variation 

may be clinically superior to the first drug m ; 

• if the drug is intended for a subset of persons with a particular disease or 

condition, a demonstration that the subset is medically plausible; 

• a summary of the regulatory status and marketing history of the drug in 

the USA and foreign countries; 

• documentation confirming one of the two abovementioned criteria; 

The OOPD must formulate an answer within 60 days following the request. 

The designation will give the sponsor benefits to develop a drug for a rare disease or 

condition. There are five incentives: 

• tax credit of 50% for costs of clinical research undertaken in the USA; 

• access to the OODP’s clinical research grants program (even if the 

designation has not yet be obtained) 

(http://www.fda.gov/orphan/grants/index.htm); 

• marketing exclusivity for 7 years; 

• waiver of FDA user fees (always granted in the US. In the EU this in on 

request in EU and only for 50%); 

• Development and Regulatory assistance. 

m Clinically superior is defined as having greater effectiveness or greater safety in a substantial portion of 

the target population or demonstration that the drug makes a major contribution to patient care (FDA’s 

orphan drug regulations (21 C.F.R. Part 316))


Other support measures are: 

• Compassionate use 

• Fast track approval for a drug if (1) the condition is serious or lifethreatening 

and (2) there is an unmet medical need for this condition. 

This measure does not exist as such in the EU: an expedited review or 

accelerated marketing approval is possible. 

• Paediatric developments are exempted from user fees if they meet the 

criteria: paediatric patients constitute a medically plausible subset of 

patient population. 

Unlike in the EU, there is no guidance for clinical trials in small populations. 

A new similar drug can not obtain the same Orphan Designation unless it proves to 

have a clinical superiority. Clinically superior means that a drug is shown to provide a 

significant therapeutic advantage over and above that provided by an approved orphan 

drug (that is otherwise the same drug) by showing a greater effectiveness, a greater 

safety or making a major contribution to patient care. 38 

The marketing exclusivity is granted for seven years (instead of ten years in the EU), but 

this can be shortened if one of the following criteria applies (Section 316.31 of 21 

CFR): 38 

• the Orphan Designation is withdrawn or revoked by the FDA; 

• the marketing approval is withdrawn; 

• the sponsor having the exclusive approval agrees with the withdrawal; 

• or the sponsor can not provide sufficient quantity of the drug. 

Figure 3.10 : Orphan-drug designations – by calendar year 

140 

120 

100 

80 

60 

40 

20 

0 

53 

Number of approved Orphan Drug Designations 2000-2006 

87 

72 

110 

121 122 122 

2000 2001 2002 2003 2004 2005 2006 

[Source]: Based on Lewis DY. FDA Office of Orphan Products Development - Update 2007. 

NORD Corporate Council Meeting 21 May 2007. Available from 


The sponsor will within 14 months after the designation date and annually thereafter 

until marketing approval submit a brief progress report to the OOPD (Section 316.30 

of 21 CFR) (as in the EU). 38 

EMEA and FDA have developed a common EU/US Orphan Drug Application, but the 

assessments of both agencies remain different. 

New is the paediatric drug development. A paediatric indication may be considered an 

orphan indication: the same criteria and incentives apply. But the incentives can only be 

used for the clinical paediatric drug development and the marketing approval can only 

be used for a paediatric indication.


3.3.3 Marketing approval 

A marketing approval is compulsory for a drug to be distributed or transported across 

the United States. As this may be necessary for clinical testing of a new drug or to 

provide treatment with a drug showing positive results during clinical testing, the 

sponsor can obtain an Investigational New Drug (IND). n Once the IND is approved by 

the FDA, clinical trials can start. 

The Marketing Approval is obtained by applying for a New Drug Application. The 

evaluation of the application is performed by the Centre for Drug Evaluation and 

Research (CDER) of the FDA and will last for ten months. Following elements are to be 

included in the submission file: 43 

• non-clinical studies; 

• clinical studies; 

• CMC information: chemistry, manufacturing and controls; 

• proposed labelling; 

• additional information. 

The drug will be approved if it demonstrates clinical benefit through clinical trials. 

There is an accelerated approval of new drugs for serious or life-threatening diseases: 

these drugs provide meaningful therapeutic benefit to patients over existing 

treatments. 44 

3.3.4 Compassionate use 

Compassionate use is a method of providing experimental therapeutics prior to final 

marketing approval for use in humans. This procedure is used with very sick individuals 

who have no other treatment options. A Treatment Investigational New Drug (t-IND) 

can be obtained regarding some conditions: 

• drug must be intended for the treatment of a serious or life-threatening 

disease; 

• no alternative drug of treatment must be available; 

• the product must be in the process of clinical trials and in an active phase 

of MA. 

3.4 EMEA-FDA COMPARISON 

The table below outlines the main differences in EMEA and FDA procedures governing 

Orphan Designation and Marketing Authorisation of orphan drugs. 

When considering applications for Orphan Designation, EMEA focuses on the health 

impact of the disease, its prevalence and treatment approaches. Although FDA also 

examines the prevalence of the disease, this is mainly considered from the perspective 

of estimating the return on investment on developing a drug for the indication. 

Furthermore, FDA applies a higher maximum prevalence for a disease to be designated 

as an orphan indication than EMEA. Unlike EMEA, the FDA does not allow 

reconsideration of an application for an Orphan Designation. 

Market exclusivity is an incentive to entice pharmaceutical companies to develop orphan 

drugs as the drug would otherwise not offer a return on investment due to the low 

prevalence of the indication. EMEA has in place a longer period of market exclusivity 

than FDA. However, the European Commission can shorten this period on the request 

of a member state . 

Both EMEA and FDA have incentives in place to apply for Orphan Drug Designation by 

offering the possibility to reduce or waive application fees; by offering assistance in 

preparing the application file; and by offering access to an accelerated review procedure. 

n http://www.fda.gov/cder/regulatory/applications/ind_page_1.htm


In the USA, a tax reduction on clinical studies of orphan drugs can be granted, whereas 

in Europe, various financial incentives are available on a national basis. 

EMEA has developed specific guidance for clinical trials in small populations, which is 

particularly relevant to the case of rare diseases and to paediatric orphan drugs. No 

such guidance has been issued by the FDA. 

In Europe, some countries have in place procedures governing compassionate use of 

orphan drugs. These procedures are outlined in the Chapter “Benchmarking of rare 

disease and drug markets in Europe”. 

45 46 

Figure 3.11: Comparison of EMEA and FDA in the field of Orphan Drugs 

EMEA FDA 

Orphan Designation - Life-threatening or chronically - Less than 200,000 persons in 

Criteria 

debilitating diseases, with the USA; or there is no 

prevalence < five per 10,000 expectation that drug R&D costs 

population; or life-threatening, for the indication can be 

seriously debilitating or serious recovered by sales in USA 

and chronic condition where, - if FDA determines that drug will 

without incentives, there not be profitable for seven years 

would be no justification for after FDA approval, regardless of 

investing in development of 

treatment 

- No satisfactory treatment 

should exist or product must 

be of significant benefit to 

those with condition 

number of patients affected 

Reconsideration of 

Orphan Designation 

application 

Yes, every 6 months No 

Prevalence Fewer than 5 per 10,000 Fewer than 6.6 per 10,000 

Institution in charge Committee of Orphan Medicinal 

Products 

Marketing 

Authorisation 

- Application for orphan 

medicinal product designation 

- Marketing Authorisation 

application for orphan drug 

Market exclusivity 10 years (12 years for paediatric 

drugs) 

Research funding Money from national authorities & 

Community grants 

Private sources 

Financial incentives Financial incentives on a national 

basis 

Maximum more or less 250,000 

patients affected or financially nonviable 

Fee waiver via request: given by 

some Member States and by EMEA 

for centralised applications 

Office of Orphan Products 

Development 

- Ask orphan drug status - 

OOPD 

- Ask Marketing Authorisation 

– one of the Centres of FDA 

7 years 

Money by National Institutes of 

Health programmes and others 

Private sources 

Tax reduction: 50% for clinical 

studies 

Maximum 200,000 patients 

affected or financially non-viable 

Always fee reduction 

Assistance with Development and Regulatory Development and Regulatory


application file 

Accelerated marketing 

procedure 

EMEA FDA 

assistance assistance 

Possible access to accelerated 

review 

Small populations Guidance for clinical trials in small 

populations 

Compassionate use - Procedure at EMEA level for 

medicinal products not yet 

having received a Marketing 

Authorisation 

- Procedure on a national level 

different per member state 

Access to fast-track 

No guidance for clinical trials in 

small populations 

A Treatment Investigational New 

Drug (t-IND) can be obtained


4 INTERNATIONAL COMPARISON OF RARE 

DISEASE AND DRUG MARKETS IN EUROPE 


The previous chapter has described the EMEA procedure from Orphan Designation to 

Marketing Authorisation and compared this with the FDA procedure in the United 

States. The present chapter describes the regulatory aspects of the rare disease and 

drug market in Belgium and in a number of other countries (i.e. France, Italy, the 

Netherlands, Sweden and the United Kingdom). A description of the regulation in each 

country is followed by a comparative analysis between these countries. 

Key points 

• This chapter examines regulatory aspects of rare disease and drug markets 

in a number of countries; 

• Regulation of the Belgian market is compared with regulation governing the 

Dutch, French, Italian, Swedish and British markets. 


First, the rare disease and drug market has been described for Belgium, France, Italy, the 

Netherlands, Sweden, and the United Kingdom. Second, a comparative analysis was 

made focussing on different relevant aspects such as the institutional context, the 

national Marketing Authorisation procedures, pricing, reimbursement procedures, 

distribution channels and prescribing processes. Various elements of the institutional 

context were explored, including centres for rare diseases and/or orphan drugs, policy 

measures supporting the development of orphan drugs, and incentives for research on 

rare diseases and/or orphan drugs. Additionally, the analysis enquired about the criteria 

for compassionate use and off-label use for orphan drugs. Pricing issues related to 

whether a country has a system of free o or fixed p pricing of orphan drugs. If fixed pricing 

exists, the criteria for price setting were examined. The mechanism for reimbursing 

orphan drugs and whether orphan drugs are fully or partially reimbursed is also 

covered. Information was gathered about the distribution channels and site of delivery 

of orphan drugs. A final issue concerned the conditions for prescribing orphan drugs. 

The countries were selected for their comparable living standards and their geographic 

proximity to Belgium. Furthermore, the chosen country panel provides insight into the 

variety of regulatory mechanisms that govern rare disease and drug markets. Finally, 

health expenditure is primarily financed by the public payer (the third-party payer or 

National Health Service) in each of these countries. 47 

A review of the international peer-reviewed literature confirmed the absence of 

scientific articles on the regulation of rare disease and drug markets. Therefore, 

information was gained by accessing documents setting out national legislation and local 

publications. In addition, a qualitative questionnaire (see annex 1.3) was completed by 

correspondents from governmental and regulatory agencies, rare disease and orphan 

drug national task forces, patient organisations, health insurance funds and members of 

the INAHTA (International Network of Agencies for Health Technology Assessment) q . 

Members of the COMP at EMEA and the European Task Force on Rare Diseases also 

provided information. 

o In a free price system, the price is set following negotiation between the government and the sponsor. 

p In a fixed price system, the price level is fixed by the government; no deviation by the sponsor is possible. 

q http://www.inahta.org/inahta_web/index.asp


The data collection relied on a literature search, a survey based on a qualitative 

questionnaire and telephone interviews with national experts. Regarding Belgium, a 

meeting took place with Pharma.be, the representative organ of the Belgian 

pharmaceutical industry in order to comprehend their point of view of the Belgian 

situation. 

Each country-specific section about the regulation governing rare diseases and drugs 

was validated by a national expert. 

Key points 

• The benchmarking exercise focused on issues related to the institutional 

context, Marketing Authorisation, reimbursement, pricing, distribution and 

prescription of orphan drugs. 

• Regulatory aspects of rare disease and drug markets were examined 

through the perusal of legal texts, the analysis of survey results, and contacts 

with national experts. 

4.3 BELGIUM 

4.3.1 Institutional context 

Belgium applies the EU definition for rare diseases. The main institutional actor in the 

Belgian orphan drug policy is the National Institute for Health and Disability Insurance 

(NIHDI). There are no official centres of reference for rare diseases, but there are 

several centres that are specialised in one or more rare diseases. Some of these centres 

are recognised by the NIHDI and work under a convention. These centres include the 

eight centres for human genetics 48 , the seven Mucoviscidose (CF) centres, eleven 

centres for metabolic diseases and six for neuro-muscular diseases. The NIHDI has 

restricted the reimbursement of some orphan drugs to prescribers belonging to one of 

the recognised centres that provide treatment. 

No specific programmes to fund research networks exist. There are not yet national 

policy measures to promote the development of orphan drugs, although there is a 

growing demand on the part of patients, the medical community and even politicians. 

Still, revenues of orphan drugs are not subject to taxation. A Pilot Group for Orphan 

Drugs (Stuurgroep Weesgeneesmiddelen) 49 was established in order to promote a 

coherent policy for orphan drugs and rare diseases. The Pilot Group comprises 

different thematic working groups composed of experts of different horizons. Discussed 

themes are survey & registries, rare diseases & costs, information & education, and 

reference centres. The Pilot Group has been integrated in the Fund Rare Diseases and 

Orphan Drugs of the King Baudouin Foundation. 


Orphan drugs obtain Marketing Authorisation through the centralised procedure at 

EMEA since 2005 (see previous chapter). Before 2005, Marketing Authorisation through 

the mutual recognition procedure was till possible. In Belgium this has been the case for 

e.g. Duodopa.


4.3.3 Reimbursement 

In order for a drug to be put on the Belgian reimbursable pharmaceutical products lists, 

the Marketing Authorisation Holder (MAH) has to submit a drug reimbursement 

request to the Drug Reimbursement Committee (DRC) of the NIHDI. Mid-February 

2009, there 39 application files had been submitted of which 36 had been examined. 32 

applications received a positive advice and four a negative r . 50 Three files were ongoing at 

that time. An application for reimbursement in Belgium can be submitted once the 

CHMP has given a positive advice, 51 but companies will do this most often only after the 

marketing authorisation was obtained. 

Figure 4.1 : Composition of the Drug Reimbursement Committee 

The Drug Reimbursement Committee is composed of 28 members: 1 

• 22 voting members: 

o 7 academics 

o 8 representatives of the sickness funds 

o 4 representatives of the physicians’ association 

o 3 representatives of the pharmacists association 

• 6 non voting members 

o 3 ministry representatives (Ministry of Health, of Social Affairs and 

of Economical Affairs) 

o 1 representative of the NIHDI 

o 2 members of Pharma.be (which is the representative organisation 

of the pharmaceutical industry in Belgium) 

If a medicinal product is not yet on the Belgian reimbursable pharmaceutical products 

lists, the patient can apply for compassionate use (see point 4.3.3.2) or for 

reimbursement through the Special Solidarity Fund (see point 4.3.3.3). 

4.3.3.1 Application procedure for reimbursement 

To be added on the Belgian reimbursable pharmaceutical products lists, orphan drugs 

follow the same procedure as the drugs of class 1 and others s (being specialties for 

which the company claims added therapeutic value in comparison to therapeutic 

alternatives) (see article 5 Royal Decree 21/12/2001) 52 , but are considered to be a 

specific category of drugs within class I. The procedure is the same, but the requested 

information is different. For example, in contrast to class I pharmaceutical products, 

drug reimbursement request files for orphan drugs do not have to include a costeffectiveness 

analysis. 

The pharmaceutical company introduces two dossiers: an application form sent to the 

secretariat of the DRC and a price demand to the Federal Public Service (FPS) 

Economy t (see point 1.3.4 of this chapter). 

r This is the situation at that specific date and includes potentially multiple applications for a same drug (e.g. 

refused, then resubmitted and either approved or not). 

s There are three added value classes in Belgium. The therapeutic value of a medicinal product is decided 

by the DRC and expressed in an added value class. 

Class I: medicinal products of which the therapeutic added value has been proved compared to existing 

therapeutic alternatives; 

Class 2: medicinal products with no proven therapeutic added value compared to existing therapeutic 

alternatives; 

Class 3: other medicinal products – categorised according to legislation. 

t FPS stands for Federal Public Service known formerly as Ministry.


Once the dossier has been received by the DRC, a period of 180 days starts within 

which a reimbursement decision has to be taken. The dossier must contain three types 

of data (art. 37, RD 21/12/2001): 

• the indication of the orphan drug as set by the Community register of 

orphan medicinal products and the important motivations on which the 

approval was based; 53 

• a copy of the demand sent to the FPS Economy; 

• a proposal regarding the reimbursement level and a justification thereof 

(including therapeutic value, budgetary impact and therapeutic and social 

needs) 52 . 

The DRC may decide to compose a group of experts to evaluate the justification of the 

reimbursement proposal. Even if not, a first temporary evaluation report will be 

elaborated by the DRC (together with the experts) and sent to the company within 30 

days. The final evaluation report is sent within 60 days of the dossier introduction. The 

company has 20 days to forward objections and remarks to the DRC, or to ask for 

more time to respond. (art. 15§1, RD 21/12/2001) 

After having received the company’s answers, the DRC prepares a temporary proposal 

(containing the added value class (i.e. class 1), the reimbursement conditions, the 

reimbursement base, the reimbursement category and the revision criteria) for drug 

reimbursement u if the proposal differs from the company’s proposal. Otherwise the 

DRC will prepare a final proposal and this within a period of 150 days following 

reception of the application. 

u This proposal will be included in Chapter IV of the Royal Decree of 21/12/2001.

Day 0 

Day 8 

Day 30 

Day 60 


Day 120 

Day 150 

Day 180 

Figure 4.2 : Procedure for the inclusion of an orphan drug on the drug 

reimbursement list 

Drug Reimbursement Committee FPS Economy 

Pharmaceutical company submits appli-cation 

form to the secretariat of DRC 

Admissibility check by secretariat: form is 

sent over to Bureau of DRC 

First scientific report written by experts and 

the Bureau of DRC 

Evaluation report written by experts in 

dialogue with the DRC 

Company receives report: can formulate 

remarks and answer DRC’s questions 

DRC prepares temporary proposal for drug 

reimbursement and informs company 

Company must react within 10 days 

DRC prepares final proposal with reimbursement 

conditions and revision criteria 

Pharmaceutical company introduces price 

demand at FPS Economy 

FPS Economy decides on the maximum price 

for the company to handle 

Notification of price to company 

Company has to inform CTG of maximum 

price within 90 days following the 

decision on price demand 

Company Minister of Social Affairs Advice of Finance inspector and 

approval Minister of Budget 

Minister takes final decision and informs company 

FPS Budget 

The inclusion on the reimbursement list is approved when the drug has a certain 

therapeutic value, being the sum of the evaluation of all the speciality’s properties 

relevant for the treatment: this is the efficacy, the usefulness, the tolerance, the 

applicability and the user friendliness. Together, these elements determine the place of 

the speciality within the therapy compared to other available treatments. The 

therapeutic value is situated at the level of morbidity, mortality and quality of life. A 

speciality has a therapeutic added value if the treatment with the concerned speciality 

has a higher therapeutic value than the recognized standard treatment.” 52 

Day 0 

Day 90


The Minister of Social Affairs will take the final decision within 180 days: he or she is 

not bound by the DRC’s advice and can take a different decision. The Minister will ask 

the advice of the Inspector of Finance and receive the approval of the Minister of 

Budget. The Minister of Social Affairs will always follow the advice of the Minister of 

Budget. 50 This process is taking place during the last 30 days of the process leaving little 

time for negotiation. The approval of the Minister of Budget is needed because of 

budgetary implications giving a de facto veto right on budgetary grounds. 

Current situation 

On the 31 st of December 2008, 31 orphan drugs were reimbursed in Belgium for a total 

of 35 orphan indications v . This includes Glivec® that is approved as a Class II drug (not 

as a Class I as all other orphan drugs). There are several non-orphan drugs that are 

reimbursed for orphan indications although they do not have the Emea MA. 

Figure 4.3 : Total number of reimbursed orphan drugs in Belgium 1999-2008 

Number of new Orphan Drugs per year 

12 

10 

8 

6 

4 

2 

0 

1999 2003 2004 2005 2006 2007 2008 

Number of new Orphan Drugs per year Total number of Orphan Drugs 

Source: NIHDI. Farmaceutische specialiteiten. 

. Accessed 2008-2009, 

1/3/2009. 

Of these 31 drugs, 30 have obtained a marketing authorisation at EU level. This means 

that as of 31 December 2008, there were 17 orphan drugs with a MA that were not 

reimbursed in Belgium. Of these 17 drugs: 

• two have been approved since then (in 2009) 

• two have been refused (Pedea and Wilzin) 

• one drug has probably not been submitted as there is an alternative on 

the Belgian market (Siklos, as Hydrea is on the market) 

Of the twelve drugs left, 3 received their MA in 2008, and one can expect the 

manufacturers will request reimbursement in Belgium during 2009. 

Orphan drugs within the therapeutic area endocrinology/metabolism account for the 

largest share in the total number of orphan drugs (35% of all orphan drugs are for 

endocrinology/metabolic conditions), followed closely by the oncology drugs (31%). 

Savene®, for the treatment of anthracycline extravasations, is included in the “other” 

category. 

v Please refer to table 9.1 in annex for the full list of orphan drugs. 

35 

30 

25 

20 

15 

10 

5 

0 

Total number of Orphan Drugs


Figure 4.4 : Reimbursed Belgian Orphan drugs by therapeutic area 

Cardiovascular 

& respiratory 

9% 

Haematology 

19% 

Nervous 

system 

3% 

Other 

3% Oncology 

31% 

Endocrinology / 

metabolism 

35% 

Source: EMEA. List of orphan-designated authorised medicines 6/11/2008. Available from 


4.3.3.2 Compassionate use and Belgian Medical Need programme 

The Law of 1/5/2006 54 provides for compassionate use, this is the treatment with drugs 

which are not yet reimbursed or available in Belgium. There are two programmes: 

• Programmes of compassionate use: making available, for compassionate 

reasons, of a medicinal product that can qualify for the centralised 

procedure to a group of patients with a chronically or seriously 

debilitating disease or whose disease is considered to be life-threatening, 

and who cannot be treated satisfactorily by an authorised medicinal 

product. The medicinal product concerned must either be the subject of 

an application for a Marketing Authorisation in accordance with Article 6 

of the European Regulation or must be undergoing clinical trials. 55 

• The Medical Need Programmes: making available a medicinal product to a 

group of patients with a chronically or seriously debilitating disease or 

whose disease is considered to be life-threatening, and who can not be 

treated satisfactorily by an authorised medicinal product. The medicinal 

product concerned must have a Marketing Authorisation but 

o either the given indication has not been authorised yet, or 

o although authorised, the medicinal product is not yet available 

on the market in this indication. 55 

The essential difference between the two programmes is that Compassionate Use 

concerns medicinal products which do not yet have obtained a Marketing Authorisation 

in Belgium, unlike the Medical Need Programme, which concerns medicinal products 

which have a Marketing Authorisation in Belgium for a given indication. 

In order for a medicinal product to be considered for compassionate use, the MAH will 

have to introduce a demand that will be reviewed and approved by one of the Belgian 

ethics committees. The compassionate use treatment will be prescribed by a physician: 

the hospital can require approval for the individual patient by the local ethics 

committee.


4.3.3.3 Special Solidarity Fund 

A patient can request reimbursement of an orphan drug or treatment unavailable w in 

Belgium through the Special Solidarity Fund (SSF), part of the NIHDI. The objective of 

the SSF is the reimbursement of medical expenses for rare diseases, rare indications and 

innovative techniques which are not (yet) refunded by the compulsory health insurance. 

The legal base is the law of 27 April 2005. 56 

Treatment costs for rare indications and diseases can be reimbursed if a number of 

criteria are fulfilled (see table below). Reimbursement will only be granted if the patient 

has been through all other reimbursement options, including all applicable legislation at 

national, European or international level. This means that reimbursement through the 

SSF cannot be obtained if the reimbursement of the orphan drug has been refused by 

the CMDOD. 

Figure 4.5 : SSF’s Reimbursement Criteria 

Type of reimbursement Reimbursement criteria 

Reimbursement of treatment The treatment is expensive. 

costs for rare indications Medical treatment is prescribed by a medical doctor specialised in 

(art. 25 bis) 

the treatment of the related disorder and authorised to practice 

medicine in Belgium. 

Medical treatment has a scientific value and effectiveness which is 

largely recognized by the medical profession. The medical 

treatment has to have outgrown the experimental phase. 

The compulsory health insurance system cannot provide an 

alternative. 

Medical treatment is used for an indication threatening vital 

functions of the patient. 

Reimbursement of 

The medical treatment is considered as being expensive. 

treatments costs for rare The compulsory health insurance system does not provide a 

diseases (art. 25 ter § 1) therapeutic alternative treatment. 

Medical treatment is used for a rare disease that threatens the 

vital functions of the patient. 

The medical treatment is prescribed by a medical doctor 

specialized in the treatment of the specific disease and authorised 

to practice medicine in Belgium. 

The medical profession recognizes the treatment as the specific 

approach for the rare disease. 

Reimbursement of cost for Treatment as a whole is expensive. 

rare diseases requiring a Treatment is related to a threat of the vital functions of a patient. 

continuous and complex The threat of the vital functions is directly and specifically a 

treatment (art. 25 ter § 2) consequence of the rare disease. 

The compulsory health insurance system does not provide 

therapeutic alternative. 

The complex treatment is prescribed by a medical doctor, 

specialized in the treatment of the specific disease and authorised 

to practice medicine in Belgium. 

Source: NIHDI. Het Bijzonder Solidariteitsfonds. Wat is de functie ervan? Wanneer en hoe kunt u 

er een beroep op doen? 2006. Available from 


14/4/2008]. 

w Whether or not this orphan drug has a MA or is reimbursed abroad.


The NIHDI body responsible for managing the SSF and taking decisions about 

reimbursements is the College of Medical Doctors Directors composed of Medical 

Doctor Directors of each national sickness fund and of NIHDI MDs. 

The patient’s Medical Doctor (MD) (a specialist) will fill out a form and hand it over to 

the health insurance institute through the local and national sickness fund. Within one 

month, the College of MD directors will examine the application and take a decision. 

The decision is transmitted to the patient and to the local sickness fund. In case of a 

positive advice, this latter will proceed to the reimbursement within fifteen days. The 

request for reimbursement must be done within three years following the end of the 

treatment. 

Figure 4.6 : Special Solidarity Fund Procedure 

Introduction 

reimbursement 

demand 

Patient 

Local Sickness Fund 

National Sickness Fund 

NIHDI/SSF – College of MD 

Directors 

Reimbursement 

decision 

NIHDI = National Institute for Health and Disability Insurance; SSF = Special Solidarity Fund 

The SSF has in 2007 reimbursed five drugs with Orphan Designation (not yet 

reimbursed as orphan drugs) for 141 patients for a total amount of € 4 084 225 (€ 

28 966 per patient). This accounts for 35% of the SSF’s budget. The table below gives an 

overview of these five drugs. From the five products, five have been approved for 

reimbursement as orphan drugs since. 

Figure 4.7 : SSF reimbursement for Orphan Drugs with MA in 2007 

Orphan drug Total NIHDI Number of patients NIHDI expenditures 

Expenditures 

per patient 

Myozyme® € 3 540 723 7 € 505 818 

Revatio® € 299 358 67 € 4 468 

Revlimid® € 141 050 57 € 2 475 

Ventavis/Iloprost® € 100 927 9 € 11 214 

Tracleer® € 2 167 1 € 2 167 

Source: NIHDI. Jaarverslag 2007 betreffende het Bijzonder Solidariteitsfonds, 2008


4.3.4 Pricing 

The pharmaceutical company introduces a price demand at the Federal Public Service 

(FPS) Economy x at the same time a reimbursement demand is introduced. This 

application consists of 51 

• name and address of the MAH; 

• name, pharmaceutical form, accurate indication and (if applicable) 

therapeutic added value of the drug; 

• a statement of registration proof, the scientific instruction leaflet and the 

public instruction leaflet; 

• a justification for the proposed price in terms of cost drivers; 

• the annual accounts of the applicant for the last three years; 

• the market and competition conditions and a price comparison with other 

EU Member States. 

The information to be provided for orphan drugs is the same as for non orphan drugs. 

Still, the evaluation might differ according to the actual information provided as there 

are no standard reporting requirements for costs imposed. 

The FPS Economy compares the given information with available data (such as other 

drug dossiers, other countries and other similar therapeutic drugs). 50 

Within a period of 90 days the FPS Economy will decide on a price and inform the 

company. The company must notify the price to the Drug Reimbursement Committee. 

The Committee takes that into account when making a reimbursement decision. 

No exchange of information takes place between the FPS Economy and NIHDI during 

this period. Following the decision, the FPS Economy will play no other role but to 

collect the manufacturers’ turnover figures. 

4.3.5 Distribution 

Most orphan drugs, except for two (Glivec and Thalidomide) are distributed through 

the hospital pharmacies. 

4.3.6 Prescribing 

The prescription of orphan drugs is subject to conditions to be found in the 

reimbursement form. Orphan drugs are part of the reimbursement category A y : these 

are drugs for severe conditions or diseases and are reimbursed at 100%. The conditions 

for reimbursement are described in the applications forms for reimbursement to be 

found in Chapter IV of the Royal Decree of 21/12/2001. 52 This chapter contains all 

drugs that receive special reimbursement conditions due to medical and/or budgetary 

reasons. 

A physician wishing to prescribe an orphan drug to a patient has to follow the 

procedure set out in Figure 4.8 in order to obtain reimbursement for this patient. The 

physician must receive the approval of a Medical Advisor of the sickness fund. This 

procedure also applies to a number of non-orphan drugs and is hence not specific for 

orphan drugs. However, in case of orphan drugs the medical advisor has the additional 

possibility to ask advice from the “College of Medical Doctors for Orphan Drugs” 

(CMDOD) if one exists for the drug. The Medical Advisor of the sickness fund can, but 

is not obliged to, request the advice of the CMDOD. 

x FPS stands for Federal Public Service known formerly as Ministry. 

y This categories define the reimbursement level and are different to the Classes mentioned above, which 

are based on the therapeutic value. Orphan drugs are automatically classified into the highest 

reimbursement category (100%) and in Class I.


Figure 4.8: Procedure to request reimbursement of orphan drug for an 

individual patient 

Compulsory: 

Application for an orphan 

drug treatment 

Optional: 

Ask for advice 

Specialist MD of the patient 

Medical advisor of the Sickness 

Fund 

“College of Medical Doctors for 

Orphan Drugs” 

Source: FOD Sociale Zekerheid. Koninklijk besluit van 8 juli 2004 betreffende de vergoeding van 

weesgeneesmiddelen. Belgisch Staatsblad, 20/07/2004. 

Individual reimbursement advice is formulated on a case by case basis by the CMDOD if 

their involvement is required by the reimbursement modalities of the orphan drug. It is 

the DRC that decides whether or not a College is established. At the end of April 2009, 

there were eighteen colleges for 31 orphan drugs. 

A College is composed of a president, four specialist MDs in the indication/disease and 

four MDs member of the DRC and mandated by a sickness fund. 20 

It is the specialist MD of the patient who completes an application form for the orphan 

drug to be found in Chapter VI of the Royal Decree of 21/12/2001 52 , and who submits 

the application to the sickness fund. It is imperative that the MD is affiliated to a 

recognised centre or a hospital for a certain disease, e.g.: 

• for metabolic diseases : a Revalidation Centre for monogenetic hereditary 

metabolic diseases; z 

• for haematology: a Centre for Haematology linked to a hospital; 

• for cardiology-pulmonology: a hospital. 

The Medical Advisor of the sickness fund will examine the demand and can decide to 

request the advice of the CMDOD. Even if the Medical advisor is not obliged to request 

the advice of the CMDOD of the concerned orphan drug, in practice he or she for each 

decision aa always asks for advice. 57 The CMDOD formulates its advice based on the 

reimbursement criteria defined in Chapter VI of the Royal Decree of 21/12/2001. 

The demand for individual reimbursement has to be introduced every year as 

reimbursement approval is only valid for a period of twelve months. 

z http://www.NIHDI.fgov.be/care/all/revalidatie/general-information/contacts/pdf/7890.pdf 

aa The pharmaceutical industry claims that not all reimbursement demands are submitted to the CMDOD. 

There is no evidence to confirm this statement.


Key points 

• In Belgium, there are no specific centres of reference, policy measures, 

research incentives on rare diseases/orphan drugs. 

• Orphan drugs are registered through the EMEA centralised procedure only. 

Specific legislation governs compassionate use of orphan drugs and there 

exists a programme for medical needs. 

• Orphan drug maximum prices are fixed by the Federal Public Service 

Economy as is the case for all drugs, independently of the reimbursement 

decision. 

• The reimbursement procedure considers budget impact, but not costeffectiveness. 

Pharmaceutical companies do not have to submit a formal 

cost-effectiveness analysis as part of a drug reimbursement request file for 

an orphan drug. Orphan drugs are fully reimbursed by the NIHDI. 

• Orphan drugs are distributed through hospital pharmacies only. 

• The prescription of orphan drugs by specialist physicians is subject to 

approval of a Medical Advisor of the sickness fund and in practice based on 

the advice of a College of Medical Doctors for Orphan Drugs. 

4.4 FRANCE bb 


Three institutions play a role with regard to orphan drugs on the French market: the 

French Agency for the Sanitary Security of Health Products (Afssaps - Agence Française 

de Sécurité Sanitaire des Produits de Santé), the High Health Authority (HAS – Haute 

Autorité de Santé), and the Ministry of Health. The HAS is a public independent 

authority having as objectives to improve the quality and security of the health services, 

to maintain a high-performance health system and to inform patients on their diseases 

and treatment. 

The institution in charge of research on rare diseases is the GIS cc – Institut des Maladies 

rares whose objectives are to define and establish a national policy for research on rare 

diseases; to mobilise the competences and to enhance multidisciplinary approaches; and 

to coordinate the research and to associate existing means. 58 

Measures taken to promote the orphan drug policy of the EU: 

• 2001: The pharmaceutical companies promoting orphan drugs are 

exonerated from the taxes and contributions pharmaceutical companies 

owe to the Sickness Insurance and the Afssaps. 59 

• 2002: A special funding for commercialised orphan drugs is integrated in 

the hospitals’ budget for innovative drugs. 59 

• 2006: Recognition of the “Fédération des Maladies Orphelines” dd as the 

only publicly recognised representative ee . 

Measures taken to increase the knowledge about rare diseases: 

• 2000-2005: the network ‘Genhomme’ was established to provide an 

answer to the scientific and economical challenges of the human 

genomics. 

• 2001: establishment of the “Plateforme Maladies Rares” grouping all 

actors devoted to patients with rare diseases. 

• 2001: establishment of the “Comité de Génétique Clinique” to support 

research and care treatment in the field of genetics. 

bb This chapter has partly been reviewed by Ms Annie Lorence of the Afssaps. 

cc Groupe d’intérêt scientifique 

dd http://www.maladies-orphelines.fr/ 

ee In French: “reconnue d’utilité publique”


A French National Plan for Rare Diseases with ten strategic priorities was published in 

2004. The aim is to assure equal access to diagnostic, treatment and care taking of 

persons suffering of a rare disease through implementation of ten strategic priorities. A 

new draft is being prepared at the moment. 

One of the strategic priorities is to enhance care management through the 

establishment of centres of reference. 60 Mid-February there were 131 centres of 

reference who were awarded the label by the Health Minister for five years. The 

centres have a double role: they are an expert centre for 1 or more diseases and they 

are a resource centre for patients coming from outside the region. A second type of 

centres are the qualified centres whose aim is to assume responsibility for treatment 

and follow-up of the patient close to their home, and to participate in the entirety of 

the centres of references’ tasks. These qualified centres take in charge patients that can 

not be treated in a reference centre. 61 

There are several incentives to stimulate orphan drug development: 62 

• Research support through national funding programmes: GIS-Rare 

diseases, Hospital Programme of Clinical Research (Programme Hospitalier 

de Recherche Clinique); 

• During development: Free scientific advice of Afssaps; 

• Budgetary incentives: tax exemption of the Sickness Insurance and the 

Afssaps. 



EMEA (see previous chapter). 


After having obtained a Marketing Authorisation of EMEA, the MAH will introduce a 

demand for reimbursement at the HAS. 

Figure 4.9 : Introduction process of orphan drug in France: 2 steps 

Source: Meyer F. Orphan Drugs: How Are They Assessed / Appraised in France? In: HAS (ed). 25 

February 2008, p.4.


The demand for inclusion on the reimbursement list is examined by the Transparency 

Committee of the HAS. The Transparency Committee renders an advice on the clinical 

added value (SMR: Service Médical Rendu) and the improvement in the clinical added 

value (ASMR: Amélioration du Service Médical Rendu) as compared with existing 

therapies. The Committee then proposes a positive or negative advice to the Health 

and Social Security Ministers relating to the reimbursement of the drug. 

There are two criteria for inclusion in the reimbursement list: 63 

1. Clinical added value: takes into account the indication (disease characteristics 

and severity) and the drug characteristics (clinical effectiveness and impact on 

public health). If the added value is insufficient, no reimbursement takes place. 

2. The improvement of clinical added value: this is the clinical improvement 

compared to existing therapies. There are five levels 

o ASMR Level I, II and III: innovative drugs (recognized added value) are 

eligible for faster access at a better price; 

o ASMR Level IV: minor improvement – product eligible for a higher 

price than comparators; 

o ASMR Level V: no improvement – reimbursement possible if costs are 

inferior to comparators. 

The Ministry of Health decides on the reimbursement of the drug. 

In figure 4.10, the first table provides an overview is given of the SMR since 2002 and of 

the ASMR for 2007. Since 2002, 35 orphan drugs have received a favourable clinical 

added value. The second table shows that orphan drugs score better on the ASRM level 

than non-orphan drugs. 

Figure 4.10 : Overview of the assessment of orphan drugs in France 

SMR (since 2002) 

Year N 

2002 1 

2003 6 

2004 5 

2005 3 

2006 6 

2007 12 

Total 35 

Level ASMR 2007 for orphan and nonorphan 

drugs 

N % OD % all drugs 

ASMR I Major 3 10% 1% 

ASMR II Important 13 43% 4% 

ASMR III Moderate 8 27% 6% 

ASMR IV Minor 4 13% 5% 

ASMR V No improvement 2 

30 

7% 84% 

Source: Meyer F. Orphan Drugs: How Are They Assessed / Appraised in France? In: HAS (ed). 25 

February 2008, p.12. 

The Transparency Committee also: 64 

• Makes an estimate of the target population; 

• Gives advice to the prescribers on the drug’s place within therapy; 

• Determines the limits of the currently available data and request 

additional data.


Another actor intervening in the reimbursement decision is the National Health 

Insurance Fund. It 

• fixes reimbursement rates for drugs within the conditions and limits fixed 

by the State; 

• classifies drugs into categories on the basis of the National Health 

Authority assessment of the clinical added value; 

• decides which acts and performances will be reimbursed. 65 

4.4.3.1 Compassionate use 

Orphan drugs can be delivered to patients without having first received a Marketing 

Authorisation, through clinical trials, authorisation for temporary usage (ATU) and 

hospital preparations. Experimental drugs can be administrated in clinical trials and to 

hospital preparations for which there is no pharmaceutical speciality available or 

adapted. Furthermore, innovative drugs may receive an ATU of the Afssaps if there is a 

public health need. The drug must fulfil several criteria: it is a treatment for a serious or 

rare disease; no therapeutic alternative is available; it has a positive risk/benefit and it is 

for temporary use. The evaluation will take into account aspect of the drug (quality, 

security and efficacy) and the medical environment (disease and alternatives). Examples 

or medicinal products that use the ATU are: Thalidomide®, Aldurazyme®, Cerezyme®, 

Fabrazyme® and Carbaglu®. 66 

4.4.3.2 Off-label use 

4.4.4 Pricing 

Off-label use of an orphan or non-orphan drug is possible for a rare disease (as defined 

by the European Regulation 141/2000 5 ) if the medicinal product is listed in an advice or 

recommendation relating to a category of sick persons of the HAS (Article L162-17-2-1 

of the Social Security Legal Code). 

The treatment and reimbursement are decided by decree of the Ministers of Health and 

Social Security and following advice of the National Union of the Sickness Funds. The 

specialities, products or services being the subject of the decree can be dealt with only 

if their use is essential to the improvement of the health of the patient or to avoid its 

deterioration. They must moreover be registered explicitly in the protocol of care. 

The Economic Committee for Health Products of the Ministry of Health negotiates the 

price of an orphan drug with the pharmaceutical company in order to reach an 

agreement on the price-volume. 67 

Price setting for an orphan drug takes into account: 63 

• the improvement in clinical added value of the medicine; 

• the prices of medicines serving the same therapeutic purpose; 

• forecasted or recorded sales volumes; 

• foreseeable and actual conditions of use of medicine; 

• the National Health Authority assessment; 

• reference prices in Ireland, Italy, Portugal, Spain and the EU. 68 


Orphan drugs are distributed through the community pharmacies or the hospital 

pharmacies. For one third of the orphan drugs prescription by and delivery through the 

hospital pharmacy for hospitalised patients is obligatory.



The orphan drug will be reimbursed if the rare disease is one of the indications. 

Otherwise, the drug can still be prescribed, but it is not reimbursable. 59 

The prescription must be delivered by a MD specialist either working on its own 

(minority of orphan drugs) or within a hospital (majority of orphan drugs). But the first 

prescription has to be delivered by a centre of reference (if such centre exists for the 

disease at issue). 

It is the Social Security that is in charge of reimbursement. 

Key points 

• France has in place specific centres of reference, policy measures, and 

research incentives on rare diseases/orphan drugs. 

• Orphan drugs are registered through the EMEA centralised procedure. 

Specific legislation governs compassionate use of orphan drugs. 

• Orphan drug prices are fixed by the Economic Committee for Health 

Products of the Ministry of Health. 

• The reimbursement procedure considers the clinical added value. Orphan 

drugs are fully or partially reimbursed by social insurance. 

• For some orphan drugs, prescription and delivery through hospital 

pharmacies is compulsory. 

4.5 ITALY ff 


The Italian Medicines Agency (AIFA - Agenzia Italiana del Farmaco) is in charge of the 

introduction of orphan drugs on the Italian medicine market. The AIFA has also set up a 

fund of around 45 millions Euro a year, of which half is used to the reimbursement of 

orphan and ‘life saving’ drugs and the other half is aimed at supporting independent 

research, drug information programs and pharmacovigilance. 69 This funding program 

for independent clinical research on drugs is open to researchers working in public and 

non profit institutions. One of the research areas of the program is dedicated to orphan 

drugs for rare diseases. At the start of 2009, three calls for proposals (2005-2007) have 

been concluded and 69 studies have received funding in the area of rare diseases. 

Several incentives for promoting non-profit research were issued in an ad hoc 

regulation of 2004: 

• the fees of the ethics committee are waived; 

• the National Health Service (NHS) can reimburse the study drugs; 

• and patients’ insurance costs are financed by the study institution. 69 

In every Italian region there are one or more Regional Centres, which act as reference 

centres in the region and are authorised to diagnose rare diseases and to prescribe 

orphan medicines. There is also a National Centre for Rare Diseases at the National 

Institute of Health, which coordinates the activity of the regional centres, carries out 

scientific research and public health activities, including cooperation with patient 

associations. 70 

Three National Healthcare Plans (1998-2000; 2003-2005; 2006-2008) and Regional 

Health Plans were formulated where rare diseases were addressed. The first National 

Plan has defined rare diseases as a priority for public health. 

ff This chapter has been reviewed by Dr. Pietro Folino Gallo of the Italian Medicines Agency.


A National Network for Rare Diseases and a National Registry of Rare Diseases were 

established in 2001. 60 The National Network is composed of a network of hospitals and 

referral centres organised by region where patients can be diagnosed and treated for 

free for about 500 rare diseases. The aims 71 of the Network are: 

• Prevention: implementation of prevention activities, 

• Surveillance: develop epidemiological surveillance, 

• Diagnosis: implement both diagnosis and care intervention, 

• Treatment: improve health operators’ training, 

• Promote citizens information. 

The National Registry of Rare Diseases is to be completed by regional centres. The 

registry’s general objectives are national and regional health planning and surveillance of 

rare diseases. The specific objectives are the estimation of incidence and/or prevalence, 

the definition of standardized diagnostic and therapeutic protocols, and the 

improvement of the collaboration among health care operators. 





Compassionate use of orphan drugs waiting for approval is possible and financed 

through a special fund called “Fondo AIFA 5%”. The aim of this fund is threefold: to 

improve knowledge on efficacy and safety of orphan drugs; to improve knowledge on 

efficacy and safety of non-licensed / non-marketed orphan drugs and to promote access 

to orphan drugs waiting for a Marketing Authorisation. 72 

This not only applies to orphan drugs, but also to trials on rare diseases. 

In 2008, four orphan molecules were reimbursed by the NHS through the Fondo AIFA 

5%. 

4.5.2.2 Off-label procedure 

Italy also knows an off-label procedure regulated by Law 648/96. The Technical 

Committee of the AIFA can include a given medication into a special list allowing it to 

be prescribed at NHS (National Health Service) charge, if for a specific disease there is 

no therapeutic alternative. There are three types of medical products that can be 

included: 

• innovative drugs whose sale is authorised abroad, but not in Italy; 

• drugs not yet authorised but which underwent clinical trials; 

• and drugs to be used for a therapeutic indication other than the one 

which has been authorised. 

At present fourteen orphan molecules are reimbursed for rare diseases in off-label use 

by the NHS. 73 


Orphan drugs that have obtained an EMEA Marketing Authorisation can apply for 

reimbursement in Italy. 

In order to be reimbursed, any medical products, including orphan drugs, has to meet a 

number of criteria: 

• it covers an unmet need being a relevant disease without any efficient 

therapy; 

• existing therapies for a relevant disease are not satisfactory; 

• the product has a better benefit-risk ratio than existing therapies; 

• it has a socio-economic benefit. 72


These criteria are evaluated at the Scientific-Technical Committee (Commissione 

Tecnico-Scientifica) and at the Pricing and Reimbursement Committee. Both these 

Committees are consultative bodies within the Italian Medicines Agency. 

Because, by definition, an orphan drug covers an unmet need, most of the orphan drugs 

are at the charge of the Italian NHS. 

Figure 4.11 : Availability of licensed orphan drugs in Italy (October 2007) 

70 

60 

50 

40 

30 

20 

10 

4.5.4 Pricing 

0 

68 

21 

Reimbursed and 

marketed 

6 

2 

Reimbursed, but not 

marketed 

% Number of molecules 

26 

8 

Not available 

Source: Folino Gallo P. Orphan Drugs in Italy. Accommodating orphan drugs: balancing innovation 

and financial stability. Accommodating orphan drugs: balancing innovation and financial stability; 25 

February 2008; London. 

Two committees of the Italian Medicines Agency are involved in the pricing and 

reimbursement procedure of medical products. The Scientific-Technical Committee 

takes decisions if a medical product can be reimbursed and positive list revisions, while 

the Pricing and Reimbursement Committee assesses the applications and negotiates 

with the MAHs according to the mandate received by the Scientific-Technical 

Committee. 

The procedure for pricing pharmaceutical products reimbursed by the NHS is fixed by 

law. First, the Scientific-Technical Committee decides whether or not a product can be 

reimbursed. If yes, a price negotiation takes place between the Pricing and 

Reimbursement Committee and the MAH. If the negotiation turns out positively, the 

product will be reimbursed. 

The product will then be listed in one of three drug classes: class A includes essential 

products and products for chronic diseases that are 100% reimbursed by the NHS; class 

H includes products that are 100% reimbursed through the hospital; and class C 

includes all other products which are not reimbursed because the health authorities 

intend to discourage their use (these products have a low evidence level and/or a low 

benefit / risk ratio). 

Medicines included in class C are for example antiobesity agents and benzodiazepines. 

Products for minor ailments are not reimbursed. 

Products of class C can still be used for free at a hospital level.


Price determination criteria are: 68 

• the efficacy of the product in relation to existing therapies, taking into 

account its degree of innovation, the clinical relevance, incidence and 

prevalence of the disease it intends to threat, possible reductions in 

hospitalisation, and quality of life improvements; 

• price comparisons with other countries (but a formal external price 

reference system was withdrawn in 2004); 

• forecasts of sales, including revenues derived from licensing agreements; 

• financial factors, related investment, spill over effects on employment, and 

exports. 

Prices are generally revised after two years, but both AIFA and company can at any 

moment request a revision of the contract. The company can even lower the price 

without permission, for instance after patent expiration and the introduction of a 

generic competitor, but a notification of the new price is needed. 


Orphan drugs are distributed through hospital and community pharmacies, and by 

health authorities. 


The orphan drug is prescribed by a specialist MD member of a centre of reference. 

A control mechanism exists for some rare diseases under the form of national registers 

(which are not much populated). AIFA also has a tracking system (traceability) for 

monitoring the movement of every pack (including orphan drugs) from the 

manufacturer via the wholesale to the hospitals and pharmacies. Some regions have 

local systems to match the prescriber/dispenser and the patient. 

Figure 4.12 : Orphan Drugs subjected to registration 

Aldurazyme® Orphan Drug Register 

Cabarglu® Orphan Drug Register 

Myozyme® Orphan Drug Register 

Somavert® Orphan Drug Register 

Ventavis® Orphan Drug Register 

Zavesca® Orphan Drug Register 

Nexavar® Oncologic Register 

Xagrid® Oncologic Register 

Sutent® Oncologic Register 

Source: Folino Gallo P. Orphan Drugs in Italy. Accommodating orphan drugs: balancing innovation 

and financial stability. Accommodating orphan drugs: balancing innovation and financial stability; 25 

February 2008; London. 

Conditions may be applied to the prescription of orphan drugs. One of these conditions 

is the registration of the treatment into a national register (especially for cancers). This 

means that the hospital doctor must list the patient into the register and complete the 

appropriate form (registration, treatment start, follow-up, …). Hospital pharmacists can 

dispense the orphan drugs only upon a written request with attached the register 

sheet. 69 

In some regions a dispensation fee of around 2 Euro is imposed, but patients with a rare 

disease are generally exempted from this fee.


Key points 

• Italy has in place specific centres of reference, policy measures, and research 

incentives on rare diseases/orphan drugs. 


Specific legislation governs compassionate use and off-label use of orphan 

drugs. 

• Orphan drug prices are fixed by the Pricing and Reimbursement 

Committee. 

• The reimbursement procedure considers budget impact and costeffectiveness. 

Orphan drugs are fully reimbursed by the National Health 

Service. 

• Orphan drugs are distributed through hospital and community pharmacies, 

and by health authorities. 

• The orphan drug is prescribed by a specialist MD member of a centre of 

reference. Conditions, such as registration of the treatment in a national 

register, are applied to the prescription of orphan drugs. 

4.6 THE NETHERLANDS gg 


The applicable rare diseases definition in the Netherlands is the EU definition. 

The institution in charge of rare diseases is the Ministry of Health. 

There are no official centres of rare diseases, but the eight university medical centres 

fulfil the role of main clinical expertise centres for specific rare diseases and can function 

as centres of specific rare diseases. For some rare diseases also other (top clinical) 

hospitals may function as centres for rare diseases. 

Several policy measures were taken in order to promote the development of orphan 

drugs: 74 

• A Steering Committee Orphan Drugs was established in 2001 in order 

“to encourage the development of orphan drugs and to improve the 

situation of patients with a rare disease, especially to strengthen the 

transfer of information on rare diseases”. hh The Committee is also a 

member and work package leader of the European project European 

(European Project for Rare Diseases National Plans Development, 2008- 

2011) that is preparing recommendations for the Member States on how 

to write a national plan on rare diseases and orphan drugs. 

• An orphan product developer was appointed in 2006 within the Dutch 

Organisation for Health Research and Development (ZonMw) ii to inform 

academia and enterprises (especially SME’s) about the European 

Regulation on Orphan Medicinal Products in an active way (by means of 

visits, seminars, articles, etc.). This person (R. de Rue) has been appointed 

for four years. After that it will be examined if the function can be handed 

on to the Medicines Evaluation Board or to an industry platform. 

gg This chapter has been reviewed by Dr. Sonja van Weely of the Dutch Steering Committee Orphan Drugs 

and Dr Gepke Delwel of the Health Care Insurance Board 

hh www.weesgeneesmiddelen.nl 

ii www.zonmw.nl


• A PhD student (H. Hoekstra) was appointed in 2005 in order to study the 

factors of success and failure in orphan drug development and this in close 

collaboration with the Steering Committee and the orphan drug 

developer. 75 

• The Dutch registration fee for a medicinal product can be waived if the 

medicinal product is already registered in one or several other EU 

Member States and the prevalence of the indicated disease is less than 1 

in 200,000 inhabitants in the Netherlands. 

• In 2007 a new research programme for rare diseases and orphan drugs 

was developed in order to develop therapies for rare diseases, but no 

formal decision of the Ministry of Health on the funding of this 

programme has been taken until now. 

• An Orphan Drug Designation Support Programme was launched in 

January 2009: Dutch enterprises can apply for a grant to compensate the 

application costs for the EMEA Orphan Drug Designation. jj 

• In April 2009 the Dutch Orphan Registry Consortium was launched, a 

multidisciplinary group that will use best practices to build a registry 

frame work for inborn errors of metabolism. 

The Netherlands (represented by Zoom and the Steering Committee) are partner in E- 

Rare (ERA-Net for research programmes on rare diseases) 69 , a research network 

funded by the European Commission, providing a setting to bring together clinicians and 

scientists and gather research infrastructure, patient cohorts and related biological 

material on a European scale. Zoom is the leader of work package 5 that focuses on the 

opening of programmes to encourage a multidisciplinary approach. 

Zoom provides funding through several research programmes for research on rare 

diseases, e.g. 

• The Innovative Research Incentives Scheme; 

• The Gene Therapy subsidy scheme. 

Information on rare diseases and orphan drugs is disseminated by different actors: 

• Royal Dutch Society for Pharmacists (KNMP) created the website 

www.farmanco.knmp.nl where information on European registered 

orphan drugs can be found with information on their reimbursement in 

the Netherlands; 

• Patient organisations for (a group of) rare diseases (they can obtain 

funding indirectly from the Ministry of Health). 


There is no national procedure of Marketing Authorisation for orphan drugs. All orphan 

drugs have to be registered at the EMEA, but the Medicines Evaluation Board (MEB) is 

involved in evaluating orphan drugs for the EMEA. As an independent medicinal 

products knowledge centre, the MEB evaluates the balance efficiency-safety (this is 

efficiency, risks, quality) of drugs for humans and animals, thus the advantages versus 

disadvantages. 76 The MEB’s report contains product information for MD and pharmacist 

and an instruction leaflet for the patient. The MEB will continue to follow-up 

information on the drug even after it entered the market. 

jj http://www.zonmw.nl/nl/subsidie/subsidiekalender/subsidieronde/item/subsidieregeling-orphandesignation-dossier-odd-support/


Compassionate use 

There is no specific policy for orphan drugs, but there is a general policy for 

compassionate use. In exceptional cases, compassionate use is possible if: 77 

• There is a MD declaration (named patient); 

• It concerns a serious condition for which no alternative drug is on the 

market and of which the drug is awaiting a Marketing Authorisation. In 

that case, the MAH can apply for ‘the compassionate use programme’. 

Off-label use 

The off-label procedure is the same for orphan drugs and non-orphan drugs. Off-label 

use is accepted if scientific evidence attests of an added value of the treatment with the 

drug, the drug is rational and justified, but which has not (yet) been evaluated by the 

MEB. 78 The patient must be informed of the off-label treatment. 78 


Extramural drugs, i.e. drugs that are prescribed by General Practioners and are used in 

the out-patient setting, can apply for reimbursement after the registration. All 

manufacturers do apply for reimbursement at the Ministry of Health. Consequently, the 

Health Care Insurance Board (HCIB) will perform the assessment and appraisal 

procedure for the drug based on the submitted dossier by the manufacturer. Most 

drugs are reimbursed; co-payments are possible but are rare in the Netherlands. 

Intramural drugs or hospital-based drugs i.e. drugs that are prescribed by medical 

specialists within hospitals are paid by the hospital budget. All medical products that are 

included in the official treatment guidelines of the physicians are available to patients and 

have to be paid for by the hospitals. Since hospital budgets are limited, it is difficult to 

ensure equal access of expensive drugs to all patients. To overcome this ‘postcode 

prescription’ by hospitals, policy measures have been issued. Through these policy 

measures expensive hospital-based (orphan) drugs can apply for additional funding. 

Orphan drugs that are listed on the policy measure will get a full funding, so the costs 

for these drugs are fully covered by means of those additional budgets. In case of 

expensive hospital based drugs a 80% funding is provided to the hospitals. Hospitals can 

apply for additional funding at the Dutch Care Authority (NZa). The HCIB will 

subsequently assess and appraise the request based on the submitted dossier by the 

applicant (hospitals, physicians and manufacturer are involved). The additional funding is 

always conditional, i.e. temporally, additional information needs to be collected through 

outcomes research. After three years a reassessment takes place in order to assess 

whether listing / funding will continue. 

The assessment and appraisal procedures for extramural and intramural drugs are 

different: reimbursement versus additional funding and assessment versus a two tiered 

process based on coverage with evidence. The assessment criteria are not very 

different. For extramural drugs the HCIB assess the therapeutic value of the drug in 

comparison with the existing standard treatment - assessment of the place of the new 

drug in the therapy; the cost-effectiveness of the drug and the budget impact of the drug 

for the pharmacy budget. For intramural drugs, the assessment criteria for temporally 

listing are the therapeutic value, the cost prognosis, the cost-effectiveness indication 

and the proposal for outcomes research. After three years the reassessment criteria 

are: the therapeutic value; the actual costs of the medical product; the costeffectiveness 

and the efficient prescription. The efficient prescription of the drug in 

Dutch hospitals is based on data collected through outcomes research in the Dutch 

clinical practice. Also the cost-effectiveness will be based on those data, in addition to 

other data sources like the clinical registration trials.


4.6.3.1 Extramural treatment 

In order to be included in the Medicine Reimbursement System (GVS), by which 

extramural drugs are reimbursed, the manufacturer must formally request a submission 

for reimbursement at the Ministry of Health. The HCIB will subsequently perform the 

assessment and appraisal based on the submitted dossier by the manufacturer. The 

director of the HCIB (or the Board of the HCIB) will give a motivated advice to the 

Minister of Health regarding reimbursement of the drug in the reimbursement system 

and on what list the drug should be placed. The reimbursement system contains a 

positive list of all reimbursed drugs. List 1A consists of groups of medical products that 

are interchangeable, for each group a reimbursement limit exists (reference price 

system). List 1B consists of unique medical products; no reimbursement limit exists for 

those medical products although prices are restricted due to the Act on Medicine 

prices (the price of the drug in neighbouring countries is taken as a reference). Both for 

drugs listed on list 1A and for those listed on list 1B special conditions for 

reimbursement may exist; these are listed on list 2. For example the drug is only 

reimbursed for a small group of patients, or must be prescribed by a specialist. 

Next to the reimbursement conditions on List 2 health care insurance companies may 

also give restrictions , e.g. that the medicine may only be prescribed by a specialist or a 

specific prescriber (e.g. a specialist with experience in a particular disease). 

Based on the EU transparency regulation, the assessment and appraisal procedure 

followed by the decision of the Minister of Health may last 90 days. In practice, these 

time lines are in general met for drugs listed on list 1A, the ones listed on list 1B may 

take longer especially when special conditions (list 32) are involved. An ongoing 

assessment procedure can be suspended for three months on request of the MAH in 

case time is needed to collect necessary information for the assessment of the drug. 

The procedure is the same for orphan and non-orphan drugs. The evaluation procedure 

is done by the Committee for Pharmaceutical Aid (CPA) of the HCIB and is composed 

of three parts corresponding to the three components of the application file: the 

pharmacotherapeutic (therapeutic value) evidence, the pharmaco-economic evaluation 

(cost-effectiveness) and the budget impact provided by the MAH. The CPA will first 

assess if the drug is interchangeable or not (this means that an alternative is available). If 

yes, the drug will be included on List 1A. If not interchangeable, the CPA judges the 

therapeutically added value and the cost-effectiveness of the product. It will therefore 

look at the added therapeutic value (assessing the pharmatherapeutic evidence), the 

cost-effectiveness (assessing the pharmaco-economic evaluation) and the budget 

impact kk 79 80 

. If these criteria are met, the product can be included on List 1B. 

If the indication is a rare disease and no alternative treatment as is the case for most 

orphan drugs, the MAH may ask for dispensation of the pharmaco-economic evaluation. 

This request is judged by the HCIB and is frequently given. A dispensation may also be 

asked for drugs that have a low budget impact (€500,000 annually). 

kk The budget impact takes into account (among other things): the number of patients; possible new 

alternatives; the drug’s market share; the possible off-label use; and applicable costs.


4.6.3.2 Intramural treatment 

Due to limiting hospital budgets equal access to medicines became hampered, especially 

for the treatment of certain cancers. To overcome the postcode prescription additional 

funding is provided through the following policy measures: ll 

• Policy measure “Expensive drugs” for hospitals: 80% reimbursement if 

purchase costs of a specific mm orphan drug account for more than 0.5% of 

the total drug cost of all hospitals on a macro level. 

• Policy measure “Orphan drugs” for academic hospitals: if the orphan drug 

costs account for more than 5% of the hospital’s drug budget, the surplus 

will be fully reimbursed to the hospital. 

These policy measures provide provisional funding for three years (temporary listing) 

and require collection of more evidence on the clinical and cost effectiveness of drugs 

fitting in either group through outcomes research. After maximum three years, the 

HCIB re-appraises the evidence that has been developed as a result of the additional 

studies, and on this basis it reviews its decisions on the product listing. When the 

evidence meets the expectations the drug will be kept on the list (definitive listing). This 

research fosters the development of expertise for specific rare diseases: a special 

research programme at ZonMw has been dedicated to fund research on effectiveness of 

expensive (innovative) drugs and expensive orphan drugs and research on development 

of methodology for Health Technology Assessments. Funding of the first projects in this 

research programme has started in 2008, so there are no results as yet. 74 

In 2005, a new instrument for performance-oriented costing system for hospital care 

and for medical mental health care was introduced for hospital treatments, the 

Diagnosis and Treatment Combinations (DTC). A DTC includes all the activities and 

actions performed by the hospital and medical specialist in response to the patient’s 

need for care. Within a DTC, hospital output prices are determined based on actual 

production costs. The DTC costs are reimbursed by the patient’s insurance company. 

For rare diseases there are not many diagnosis and treatment combinations and 

therefore, in many cases, hospitals are responsible for identifying and funding (from 

their budget) the treatments outside the DTC provided to patients. 74 

4.6.3.3 Current situation 

Of the 47 orphan drugs having received a Marketing Authorisation of the EMEA: 

• Eight orphan drugs are financed under the “Orphan Drugs” policy rule 

and one drug has applied for this; 

• One orphan drug is financed under the “Expensive drugs” policy rule; 

• Five orphan drugs are included on List 1A (reimbursement with 

conditions); 

• Eighteen orphan drugs are included on List 1B (100% reimbursement); 

• Eight orphan drugs are available, but not reimbursed; 

• Three orphan drugs still have to apply for reimbursement or are ongoing. 

This means that of the 47 EMEA orphan drugs, only three are not available in the 

Netherlands. 

ll 

These policy rules have been developed in order to ensure equal access of drugs to patients across 

hospitals in the Netherlands. 

mm Most orphan drugs apply for the policy measure for orphan drugs in order to obtain full funding. It is 

possible to apply for the policy measure on expensive drugs.


4.6.4 Pricing 

There are two mechanisms to regulate the price of drugs. The price of orphan drugs is 

regulated in the same way as non-orphan drugs. 

One mechanism is the incorporation of drugs in the Medicine Reimbursement system in 

case of extramural treatment. Specific clusters of drugs that are assumed to be 

therapeutically equivalent are listed on the so-called List 1A. A maximum level of 

financing is established for each cluster on the List A. List 1B products are drugs used 

for extramural treatment that do not have a therapeutically equivalent and do not have 

a maximum level of price. Until now most orphan drugs that are used for extramural 

treatment are on List 1B. The price is in this case considered together with the 

reimbursement decision. 

The second mechanism is the Regulation on maximum prices of medicinal products that 

fixes the maximum price that a manufacturer can ask for a medicinal product (listed in 

List 1A). The average prices (ex-factory prices) of Belgium, UK, Germany and France 

are used to calculate the maximum price scheme. A maximum price is set for each 

product with a given active substance, strength and formulation (constituting clusters of 

products). 74 

A price revision takes place every six months according to a basket of prices from 

Belgium, UK, Germany and France. The inclusion of UK influences the basket because of 

the value of the pound. This mechanism does not apply to the majority of orphan drugs 

as they fall under list 1B. 

The Regulation on maximum prices holds also for those medicinal products that are 

used for treatments within hospitals and that are either also used extramural treatment 

or are placed on the policy rule on Expensive medicines or on the policy rule of Orphan 

drugs. 



Orphan drugs are distributed through hospital and community pharmacies. 

The first prescription will be issued by the specialist physician or general practitioner. 

Different reimbursement procedures apply whether the drug is prescribed for home 

treatment (extramural) or is administered within the hospital setting (intramural). 

Home treatment costs are reimbursement by the Medicines Reimbursement System. 

The reimbursement level depends of whether the drugs are included on list 1A or on 

list 1B. Drugs listed on list 1B are 100% reimbursed, while there is a maximum 

reimbursement for each cluster of interchangeable products on list 1A. The patient will 

have to pay the surplus above the maximum reimbursement. 

Hospital treatment costs are (partly) taken in charge by the hospital’s budget. 

In case of off label use, reimbursement is automatic for a disease with prevalence less 

than 1:150,000 inhabitants. 

In some cases restrictions are imposed on the reimbursement of orphan drugs. The 

reimbursement conditions to be found in list 2 of the Law Care Assurance are a first 

type of restriction. A condition can be that the drug is only reimbursed for a specific 

indication, making it unavailable for off-label use. For example, miglustat can only be 

reimbursed if the patient has Gaucher type 1 and he or she can not be treated with 

imiglucerase. A second type of restriction is imposed by the health care insurance 

companies. For example, the medicine can only be prescribed by a specialist or a 

specific prescriber. 74


Key points 

• The Netherlands have in place policy measures and research incentives on 

rare diseases/orphan drugs. There are non-official centres of reference. 



drugs. 

• There are several mechanisms to fix prices of orphan drugs. 

• The reimbursement procedure considers budget impact and sometimes 

cost-effectiveness. Often, dispensation for economic evaluation is given. 

Orphan drugs are fully or partially reimbursed by social insurance. 

• Orphan drugs are distributed through hospital and community pharmacies. 

• The orphan drug is prescribed by a specialist physician or a general 

practitioner. Conditions can be applied to the prescription of orphan drugs. 

• In the Netherlands, hospitals may apply for full additional funding for orphan 

drugs that are prescribed within their institution through the policy 

measure. The additional temporally funding considers therapeutic value, 

cost prognosis and outcomes research – treatment of all patients need to be 

documented in a patient registry. After three years definitive listing 

considers: therapeutic value, budget impact, cost-effectiveness and efficient 

prescription. The appraisal will be based on these assessment criteria. There 

is no official threshold for the cost-effectiveness, a range is in place, the 

acceptable cost/QALY value will be balanced with other criteria depending 

on the individual case. In case of orphan drugs the therapeutic value, the 

severity of the disease and the efficient prescription will be important for the 

decision on definitive listing/ funding. 

4.7 SWEDEN nn 


The institution in charge of providing information on rare diseases is the Swedish 

National Centre for Rare Diseases. 

Reimbursement decisions are taken by the Dental and Pharmaceutical Benefits Board 

(DPBB), a governmental agency deciding whether or not a dental or pharmaceutical 

product will be subsidised by the State. 81 

There are specialised centres for rare diseases in each county (on a regional level) 

concentrating on clinical care, diagnosis and treatment. 60 

The Swedish National Board of Health and Welfare applies it own definition of a rare 

disease: “a disorder causing substantial disability and affecting fewer than 100 individuals per 

million population”. 9 

There is no policy for orphan drugs and there is no specific market access procedure 

for orphan drugs. 




nn This chapter has been reviewed by Mr Karl Arnberg from the Dental and Pharmaceutical Benefits Board



The DPBB takes reimbursement decisions within a 180-day assessment period. The 

criteria are the same for orphan and non-orphan drugs being the cost-effectiveness of 

the product, the human value principle and the need and solidarity principle. The 

evidence asked is mostly the same clinical data as for the EMEA Marketing Authorisation 

procedure. Sometimes additional data is requested. 82 

The cost-effectiveness comprises a comparison of indirect and direct costs with the 

MAH’s health economics analysis. The human value principle implies equality of all 

persons and the need and solidarity principle implies that products that threat those 

with the greatest health needs take precedence. Even though cost-effectiveness is 

important for non-orphan drugs, the human value principle will prevail for both orphan 

and non-orphan drugs. 83 Cost-effectiveness must be proven, but as the threshold is 

higher for more severe diseases, a greater uncertainty is accepted if there is no possible 

way of acquiring data (e.g. due to a small patient group). 84 

The approved product is included on the List of Substitutable Products. 

Figure 4.13: Number of EMEA orphan drugs reimbursed in Sweden (2003- 

2008) 

Number of new Orphan Drugs per year 

7 

6 

5 

4 

3 

2 

1 

0 

2003 2004 2005 2006 2007 2008 

Number of new Orphan Drugs per year Total number of Orphan Drugs 

Source: Dental and Pharmaceutical Benefits Agency. Medicinal Products Database. 

. Accessed 28/4/2009. 

30 

25 

20 

15 

10 

5 

0 

Total number of Orphan Drugs


4.7.4 Pricing 

The MAH is able to set the price freely, which will be approved by the DPBB following 

the abovementioned procedure. If accepted, the product will be included on the 

positive list of reimbursement. Medicinal products can also be sold without being 

included on the positive list, but patients will have to pay the full cost. This does not 

apply to products administered through hospitals: their price is the result of a 

negotiation between the MAH and the county councils. 83 

There is no price revision procedure: if a MAH wants to increase the price, the product 

will first have to be removed from the positive list and a new request will have to be 

introduced at the DPBB (substitution system). Or in order for the DPBB to approve a 

price increase for drugs not included in the substitution system, two conditions need to 

be fulfilled: 85 

1. The medicine in the application is an urgent therapeutic alternative as it is 

used to treat serious conditions which threaten the patient’s life and health. 

There are patients who risk being without similar treatment if the medicine 

disappears from the Swedish market. 

2. There is a considerable risk that the medicine will disappear from the 

Swedish market (or that the supply will decrease sharply), if the price 

increase is not approved. 

If the two conditions are fulfilled, the MAH will not have to withdraw from the positive 

list. 



Orphan drugs are available through hospital and community pharmacies. 

The first prescription can be issued by the specialist physician or the general 

practitioner, but most patients are treated by a specialist. There are no conditions for 

prescribing orphan drugs and there is no control mechanism. Reimbursement decisions 

do not differ between individuals. 84 Conditions on reimbursement can be imposed, but 

there are no general conditions specific for orphan drugs. 

The level of reimbursement is the same for all types of drugs. Up to 900 SEK (€ 81) oo of 

accumulated total cost of prescribed drugs the patient will bears the full cost. Between 

900 and 4,300 SEK the patient will pay a part of the costs and will receive the drugs free 

of charge once the accumulated total drugs cost has exceeded 4,300 SEK. An overview 

of the share of patient co-payment is given in the table 4.15. 83 

Figure 4.14: Patient co-payments in function of the accumulated total costs 

of prescribed drugs over 12 months in Sweden 

Accumulated total costs 

of prescribed drugs 

over 12 months 

Patient copayment 

Maximum 

accumulated 

patient outlay 

over 12 months 

≤ 900 SEK 100% 900 SEK 

901 – 1,700 SEK 50% 1,300 SEK 

1,701 – 3,300 SEK 25% 1,700 SEK 

3,301 – 4,300 SEK 10% 1,800 SEK 

≥ 4,300 SEK 0% 1,800 SEK 

Reimbursement is done by the Public Social Insurance. 

oo 1€ = 11,11SEK (20/4/2009)


Key points 

• Sweden has in place specific centres of reference, but no policy measures 

and no research incentives on rare diseases/orphan drugs. 


There is no legislation governing compassionate use or off-label use of 

orphan drugs. 

• There is free pricing of orphan drugs through a system of public 

procurement at the level of county councils. 

• The reimbursement procedure considers cost-effectiveness, but not budget 

impact because decisions are taken at the country level. Orphan drugs are 

fully reimbursed by social insurance. 

• Orphan drugs are available through hospital and community pharmacies. 

• The orphan drug is prescribed by a specialist physician or a general 

practitioner. No conditions are applied to the prescription of orphan drugs. 

4.8 UNITED KINGDOM pp 


There is no specific funding for promoting the development of orphan drugs as these 

take place at a European level. Research projects to fund research networks for rare 

diseases were not identified. 

A distinction has to be made between the regulatory processes, pricing, HTA processes 

and the commissioning policies: 

• Regulatory processes: the medicine obtains a licence at EMEA level; 

• Pricing which is regulated by the Pharmaceutical Price Regulation Scheme 

(PPRS) 86 ; 

• HTA processes: Three HTA regional bodies provide guidance to the 

National Health Service on the use of health technologies based on 

appraisal of clinical and cost effectiveness evidence. 57 : 

o National Institute for Health and Clinical Excellence (NICE) for 

England. NICE produces guidance on public health, health technologies 

selected by the health ministers and clinical practice; 

o Scottish Medicines Consortium (SMC) for Scotland which reviews all 

new medicines. SMC has developed a specific policy for orphan drugs; 

o All Wales Medicines Strategy Group (AWMSG) for Wales issues 

recommendations on drugs that have not been evaluated by NICE; 

• Commissioning: Commissioning in the National Health Service (NHS) is 

the process by which it is ensured that the health and care services 

provided most effectively meet the needs of the population qq . 

The cost effectiveness threshold used by NICE to make recommendations on the most 

appropriate use of medicines within the NHS is also applicable to orphan drugs. 

Following thresholds are applied: Below a most plausible ICER of £20,000/QALY, 

judgments about the acceptability of a technology as an effective use of NHS resources 

are based primarily on the cost-effectiveness estimate (point A in figure 4.15). 

pp This chapter has been reviewed by Ms Martina Garau of the Office of Health Economics; it describes 

mainly the situation in England, unless mentioned differently in the text. 

qq The National Commisisoning Group (NCG) also has a top slice budget for therapies for very rare 

conditions. See also below.


Above a most plausible ICER of £20,000/QALY, judgments about the acceptability of 

the technology as an effective use of NHS resources are more likely to make more 

explicit reference to factors including: 

• the degree of uncertainty surrounding the calculation of ICERs 

• the innovative nature of the technology 

• the particular features of the condition and population receiving the 

technology 

• where appropriate, the wider societal costs and benefits. 

Above an ICER of £30,000/QALY, the case for supporting the technology on these 

factors has to be increasingly strong.(point B in figure 4.15) The reasoning for the 

Committee’s decision will be explained, with reference to the factors that have been 

87 88 

taken into account”. 

ICER stands for incremental cost-effectiveness ratio being the extra cost that is paid for 

each extra unit of health improvement gained by using the medicine, compared to the 

next most effective alternative. The ICER is measured in terms of the cost per QALY 

gained (quality-adjusted life year) by the intervention. A QALY gained is a year of life in 

good health a person might gain as a result of treatment. 

Medicinal products with an ICER higher than 30,000£ per QALY are usually not 

considered as cost effective. For a drug to be cost effective, it must deliver an additional 

QALY over and above treatments already available. Exceptions have been made for 

orphan drugs: for example Imatinib for the treatment of myeloid leukaemia was 

approved at a cost of 48,000£ per QALY (being the highest cost ever accepted). 89 In 

January 2009, NICE published a supplementary advice indicating that life-extending 

medicines for end of life conditions affecting small populations can be recommended by 

NICE even when they exceed the cost-effectiveness threshold of £30,000/QALY. 87 This 

advice will influence decisions on treatments for rare cancers as they fall under end of 

life conditions, but not long-term chronic rare conditions. 57 

Figure 4.15: Incremental cost per QALY gained (ICER) 

Source: Rawlins MD, Culyer AJ. National Institute for Clinical Excellence and its value judgments. 

BMJ (Clinical research ed). 2004(329):224-7. 

A debate has been going on for some years on how to define orphan and ultra-orphan 

drugs. Recently, the Health Minister stated that there is no formal classification of 

“ultra-orphan” drugs. The term has been used by NICE to indicate treatments for 

conditions with a prevalence of less than one in 50,000 in the United Kingdom.


The National Commissioning Group (NCG) of the NHS selects diseases with less than 

400 cases. Its role is to commission services for the population of England for a specific 

group of extremely rare conditions, which can include orphan drugs. 90 




The body responsible for regulatory approval in the UK is the Medicines and Healthcare 

products Regulatory Agency (MHRA) which has not been involved with orphan drug 

Marketing Authorisation, to date. 


Prescription of unlicensed drugs is accepted if three conditions are fulfilled: 91 

• It is a bona fide unsolicited order; 

• The product is formulated in accordance with the requirement of a 

doctor or dentist registered in the UK; 

• The product is for use by individual patients on their direct personal 

responsibility. 

There is not a specific procedure for compassionate use in the UK. 

4.8.2.2 Off-label use 

Off-label use is defined as the use of a licensed medicine for an unlicensed indication or 

administered via a different route. The medicine will be reimbursed if it is not 

particularly expensive. Otherwise, the reimbursement and the provision are monitored 

more strictly. The authority which monitors this is the Prescription Price Authority. 58 


4.8.3.1 Uptake of medicine on the market 

The UK has no system of reimbursement similar to the ones in other European 

countries as medicines are made available after launch and can in principle be prescribed 

by clinicians operating within the NHS as soon as the Marketing Authorisation is 

obtained. In practice, there are however mechanisms to control expenditure and a 

medicine can be appraised by one of the Health Technology Assessment (HTA) bodies 

(NICE, AWMSG, SMC), which issues guidance on its appropriate use within the NHS. 

The HTA body makes recommendations to the NHS about which drugs and treatments 

should be available. 

NICE evaluates orphan drugs using the same methods and decision criteria as for all 

technology appraisals, but a lower level of evidence may be accepted for orphan drugs. 92 

If NICE rejects a medicine, than the NHS clinicians cannot prescribe it. Technology 

appraisal consists of three steps: 93 

1. Scoping: what will be examined; 

2. Assessment of clinical and cost effectiveness: by means of a review of 

evidence and an economic evaluation (cost per QALY) conducted by an 

academic centre and the manufacturer/s. 

3. Appraisal of the assessment taking into account the opinion of consulters, 

commentators, clinical specialists and patient experts. 

While NICE assesses both old and new technologies, the SMC issues guidance on all 

newly licensed medicines, new indications and formulations. 94 The AWMSG “appraises 

new high cost, cardiac and cancer medicines for which no NICE guidance is expected for at 

least twelve months”. 95 

The SMC has adopted a policy on orphan drugs according to which orphan drugs are 

appraised in the same way as normal drugs, but modifiers are considered. 96


These modifiers are additional factors considered when orphan drugs are appraised, 

such as whether the drug: 

• treats a life threatening disease; 

• substantially increases life expectancy and/or quality of life; 

• can reverse, rather than stabilise, the condition; 

• or bridges a gap to a “definitive” therapy. 97 

The AWMSG’s criteria for ultra-orphan drugs are: 98 

• Degree of severity of the untreated disease, in terms of quality of life and 

survival; 

• Whether the drug can reverse, rather than stabilise the condition; 

• Overall budget impact; 

• Whether the drug may bridge a gap to a “definitive” therapy which is 

currently in development; 

• The innovative nature of the drug. 

The assessment of the drugs takes into account the cost-effectiveness based on the 

price decided by the MAH 63 

As of April 2008, NICE had appraised only one EMEA-designated orphan drugs, which is 

imatinib for the treatment of gastro-intestinal stromal tumours and of chronic myeloid 

leukaemia. In both cases, the treatment was recommended for use. 99 

On the other hand, SMC had reviewed 28 orphan drugs. “Almost half of them were 

rejected (13), 12 were recommended and three were recommended for restricted use, 

i.e. for patient sub-group/s within the licensed indication”. 99 

The price of medicines funded by the NHS is included in a national list of tariffs, the 

British National Formulary (BNF). Funding takes place through the budget of the 

National Health Service. 

4.8.3.2 Commissioning 

England, Wales and Scotland have each developed specific funding mechanisms for 

orphan drugs, which are broadly similar. In England, health care services, including 

medicines, for very rare diseases are commissioned by the NCG. The NCG will assess 

diseases with an incidence of less than 400 cases. 44 On a regional level, services can be 

referred to the Specialised Commissioning Groups. 

The commissioning consists of an assessment of the health service needs and the 

current service provision for the local population. Based on this assessment, the 

Primary Care Trusts (PCTs) at local level identify what type and level of services need 

to be procured in the coming year from primary care services providers, such as 

General Practitioners or pharmacists, or from secondary care institutions, such as 

hospitals and mental health trusts. 55 The PCTs are responsible for the funding. 

4.8.4 Pricing 

The pricing mechanism is the same for orphan and non-orphan drugs. 

Prices are set freely by the MAHs, but have to meet the profit control criteria included 

in the PPRS. This scheme is an agreement between the Department of Health and the 

Association of the British Pharmaceutical Industry. 86 

There are two mechanisms for price revisions: 

• “flexible pricing where a price decrease or increase by the MAH is 

possible if there is new evidence or if a different indication is being 

developed (the flexible pricing mechanism will allow to have prices which 

better reflect the drug therapeutic value); 

• patient access schemes: early access to medicines which are not in first 

instance found to be cost and clinically effective by NICE”. 100


According to the 2009 PPRS agreement, MAHs are able to modulate the list price of 

their PPRS products by changes that equate to an overall level of 3.9% in 2009. 

Price revisions take place on an infrequent basis. 



Orphan drugs are distributed through hospital pharmacies and specialist centres. 

The first prescription will be issued by the specialist physician. The prescription has to 

be consistent with the license. 

The prescription process is influenced, and therefore controlled, by the guidance, when 

available, of the HTA bodies on the use of medicines within the NHS. 

Differences in individual HTA decisions occur on a regional level as medicines are 

appraised by different HTA bodies (NICE, SMC and AWMSG) who can take different 

decisions. 

Key points 

• There are no policy measures and research incentives on rare 

diseases/orphan drugs in the UK. There are specific centres of reference for 

some orphan drugs. 



drugs. 

• Prices are set freely by the MAHs, but have to meet profit control criteria. 

• Orphan drugs are either fully or not reimbursed 

• The reimbursement procedure considers budget impact and costeffectiveness. 

Orphan drugs are fully reimbursed by the National Health 

Service. 

• Orphan drugs are available through hospital pharmacies. 

• Orphan drugs are prescribed by specialist physicians. The prescription 

process is influenced by the guidance of HTA bodies, if available. 

4.9 COMPARATIVE ANALYSIS 

Regulatory traits of the rare disease and orphan drug market in the six countries 

studied are presented in Figure 4.16. 

With respect to the institutional context, France, Italy, Sweden and (partly) the UK have 

dedicated centres of reference for orphan drugs and rare diseases. University medical 

centres fulfil this role in the Netherlands. A similar situation applies for Belgium as 

mentioned above with four networks of centres that can be considered to partially fullfil 

the role of centres of reference. In addition to European measures to promote research 

and development of orphan drugs, France, Italy and the Netherlands have implemented 

additional policy measures and research incentives for orphan drugs and rare diseases. 

Orphan drugs are registered through the EMEA centralised procedure in all six 

countries. Countries have introduced specific legislation governing compassionate use of 

orphan drugs, except for Sweden. Italy, the Netherlands and the UK have implemented 

a procedure for off-label use of orphan drugs.


Prices of orphan drugs are subject to price fixing in all countries, except for Sweden (at 

the county level) and the UK. In France, Italy and the Netherlands, prices are fixed with 

reference to, amongst other things, the price level in other EU countries. In the 

Netherlands, maximum prices are fixed for orphan drugs. In order to maximize price 

competition, prices in Sweden are determined by a system of public procurement at the 

regional level. In the UK, orphan drug prices are set freely by the MAHs, but have to 

meet the profit control criteria. 

To gain reimbursement, formal cost-effectiveness analysis is sometimes but not always 

performed for orphan drugs in the countries studied. The budget impact of orphan 

drugs is considered in the reimbursement application in all countries, except for 

Sweden. Orphan drugs are not always fully reimbursed in all countries studied. Orphan 

drugs are fully reimbursed in Italy, Sweden, Belgium and the UK. France and the 

Netherlands operate a mixed system of full or partial reimbursement. 

Orphan drugs are distributed through hospital pharmacies in all countries studied. 

Additionally, they are distributed through community pharmacies in Italy, France, the 

Netherlands, and Sweden; they are also distributed through health authorities in Italy; 

and through specialist centres in the UK. 

Orphan drugs are initially prescribed by a specialist physician or a general practitioner in 

the Netherlands and Sweden. The prescription is the exclusive responsibility of the 

specialist physician in Belgium, Italy and the UK. All countries studied impose conditions 

on prescribing orphan drugs, except for Sweden. In Italy, if an orphan drug is prescribed 

to a patient, the treatment must be registered in a national registry. Delivery of the 

drugs depends on provision of the data for the registration. This is also partly the case 

in Belgium for orphan drugs for which a CMDOD exists. In France, orphan drugs are 

reimbursed only if the rare disease is one of the indications. In the Netherlands, health 

insurance funds have the right to impose additional prescribing conditions. In the UK, 

the prescription process of orphan drugs is influenced by the guidance of HTA bodies, if 

available. 

The number of available orphan drugs per country varies: 

Belgium 31 orphan drugs reimbursed, 2 not reimbursed but 

available (2008) rr 

France 35 orphan drugs (2007) 

Italy 23 molecules (2007) 

The Netherlands 44 orphan drugs of which 36 are reimbursed (2008) 

Sweden 28 orphan drugs 

United Kingdom Information not available. All are in theory available, 

but not all are reimbursed. 

The highest availability of orphan drugs is achieved in the Netherlands and France. 

rr See table 8.1 in annex for the full overview. Drugs available for compassionate use or available but not yet 

reimbursed are not included.


Figure 4.16: Regulation governing rare disease and orphan drug markets 

Features 

INSTITUTIONAL CONTEXT 

Belgium France Italy Netherlands Sweden UK 

Existence of centres for rare diseases/orphan drugs: No Yes Yes No Yes Yes 

Policy measures to promote development of orphan drugs: No Yes Yes Yes No No 

Incentives for research on rare diseases/orphan drugs: No Yes Yes Yes No No 


Existence of national Marketing Authorisation procedure: No No No No No No 

Procedure for compassionate use of orphan drugs: Yes Yes Yes Yes No Yes 

Procedure for off-label use of orphan drugs: No No Yes Yes No Yes 

PRICING 

Pricing system: 

- Free market 

- Price fixing 

REIMBURSEMENT 

Third-party payer: 

Yes Yes Yes Yes 

Yes (county 

level) 

Yes (national 

level) 

- National Health Service Yes Yes 

- Social insurance Yes Yes Yes Yes 

Reimbursement based on cost-effectiveness: No Yes Yes Sometimes Yes Sometimes 

Reimbursement based on budget impact: Yes Yes Yes Yes No Yes 

Reimbursement level: 

- Full reimbursement Yes Yes Yes Yes Yes Yes 

- Partial reimbursement No Yes Yes 

DISTRIBUTION CHANNELS 

Delivery channels: 

- Hospital pharmacies Yes Yes Yes Yes Yes 

Yes


Features Belgium France Italy Netherlands Sweden UK 

- Community pharmacies Yes Yes Yes 

- Health authorities Yes 

- Internet 

- Other 

PRESCRIBING PROCESS 

Prescription by: 

- Specialist physician Yes Yes Yes Yes Yes 

- Nurse practitioner 

- General practitioner Yes Yes 

Existence of conditions for prescribing orphan drugs: Yes Yes Yes Yes No Yes


5 CRITICAL ASSESSMENT 


Chapter 4 has described the reimbursement procedure for orphan drugs in Belgium. 

Since 2002, the Drug Reimbursement Committee (DRC) of the NIHDI (National 

Institute for Health and Disability Insurance), the Belgian third-party payer, evaluates 

drug reimbursement requests based on multiple criteria: the therapeutic value, price 

and proposed reimbursement tariff, the importance of the drug in clinical practice, and 

the budget impact of the drug. No economic evaluation of the orphan drug is required 

for reimbursement purposes. 

The aim of this chapter is to carry out a critical assessment of reimbursement request 

files of orphan drugs that have been submitted in Belgium since end 2001, the date that 

the new reimbursement procedure (not specific to orphan drugs) came into effect ss . 

First, a qualitative overview was conducted of the reimbursement dossiers of all orphan 

drugs focusing on the evidence submitted for each reimbursement criterion. Second, a 

number of orphan drugs were selected for an in-depth analysis. A critical assessment 

provided in the context of a drug reimbursement request for these orphan drugs was 

conducted and compared with the assessment report of the DRC (see point 5.4.2). 

Key points 

• This chapter conducts a qualitative overview of the reimbursement files of 

all Belgian orphan drugs focusing on the evidence submitted for each drug 

for each reimbursement criterion. 

• A critical assessment was carried out of the scientific evidence for 8 selected 

orphan drugs and compared with the assessment report of the DRC. 


5.2.1 Qualitative overview 

The qualitative overview was based on an examination of the reimbursement request 

files of orphan drugs submitted to the DRC. The following information was extracted 

from the dossiers: description of the orphan drug; reimbursement status; therapeutic 

value and needs; budget impact; and number of registered indications. Each drug was 

identified in terms of its name, code according to the Anatomical Therapeutic Chemical 

(ATC) drug classification system 101 and supplier. The reimbursement status related to 

whether the dossier was an original application or a revision and whether 

reimbursement had been awarded. The quality of clinical evidence used to assess the 

therapeutic value of orphan drugs was evaluated by focusing on the number and design 

of clinical studies. The analysis also considered whether clinical studies had been 

published in peer-reviewed journals. The therapeutic needs for an orphan drug were 

analysed by taking into account its place in clinical practice (first- or second-line 

treatment) and whether any alternative treatment existed. The budget impact was 

determined by means of the number of patients and the cost per patient per year as 

reported in the reimbursement dossiers. Finally, the number of indications was 

reported for which the orphan drug was registered with the European Medicines 

Agency (EMEA) and for which the orphan drug sought reimbursement in Belgium. 

Companies need to submit a revised dossier to the DRC after 1.5 to 3 years following 

initial reimbursement approval (see chapter 4). Our analysis covered the finalised 

dossiers relating to the revised application of three orphan drugs, whose 

reimbursement was initially granted in 2004 and the initial application of 23 orphan 

drugs. 

ss KB 21/12/2001 tot vaststelling van de procedures, termijnen en voorwaarden inzake de tegemoetkoming 

van de verplichte verzekering voor geneeskundige verzorging en uitkeringen in de kosten van 

farmaceutische specialiteiten. Belgisch Staatsblad 29/12/2001.


5.2.2 In-depth analysis 

Eight orphan drugs were selected for an in-depth analysis. These cases were chosen to 

reflect the variety of reimbursement applications submitted to the DRC. 

5.2.2.1 Criteria for selection 

A panel of three experts agreed on the following selection criteria for cases (in 

descending order of importance): 

Criteria level 1: 

• Nature of disease: metabolism, oncology, toxicology, endocrinology, 

cardiovascular, hematology 

• Therapeutic value 

o Evidence published: yes/no 

o Number of studies and phase 1, 2, 3 or 4 

• Is it a first submission or a revision 


• Budget impact 

o Prevalence 

o Cost/patient/year 


• Supplier 

• Therapeutic need 

o 1 st or 2 nd line treatment 

o Alternative available: yes/no 

5.2.2.2 Choice of cases 

Applying the criteria and looking for the highest coverage for each criterion resulted in 

the following selection: Pedea®, Aldurazyme®; Fabrazyme®; Replagal®; Tracleer®; 

Trisenox®; Xagrid®; Zavesca®. Pedea® was a ‘negative’ case. The 7 other drugs turned 

out to be the ‘oldest’ cases. 

Together, these provide for a good spread over the different situations that can occur, 

over the natures of diseases possible, stand for a significant potential budget impact, and 

are produced by various different manufacturers. 

Figure 5.1 Overview of the eight cases 

Aldurazyme® Fabrazyme® Replagal® Tracleer® Trisenox® Xagrid® Zavesca® Pedea® 

Nature of disease metabolic metabolic metabolic cardiovascular oncology hematology metabolic cardiovascular 

Evidence published no yes yes no yes yes yes No 

Phase study 1 double-blind 1 double-blind 2x2 1x3 1x2 1x1/2 1x1/2 6 RCTs 

RCT 

placebo 

2x3 

1x4 

First or revision 2 2 2 1 1 1 1 1 

Budget impact 12 / 

50-75 / 50-75 / 300 / 9 / 11000 / 90 / 200-300 / 

(prevalence / 

cost per patient 

per year) 

€40 000 €200 000 €200 000 €39 000 €25 000 €7 500 €94 000 €381 

supplier Genzyme Genzyme Shire EGT Actelion Cephalon Shire Actelion Orphan 

Europe 

1st or 2nd line 1 1 1 1 2 2 2 1 

Alternative No Yes, Replagal Yes, Yes No Yes Yes Yes, 

available 

Fabrazyme 

Indomethacine


Key points 

• The qualitative overview extracted information about the orphan drug; 

reimbursement status; therapeutic value and needs; budget impact; and 

number of registered indications from each reimbursement dossier. 

• A number of orphan drugs were selected for in-depth analysis. They were 

selected on the basis of the nature of disease, therapeutic value, 

reimbursement status, budget impact, supplier and therapeutic needs. 

5.3 QUALITATIVE OVERVIEW OF ALL REIMBURSEMENT 

DOSSIERS 

Between January 2002 and June 2008, reimbursement dossiers of 26 orphan drugs 

submitted to the DRC have been finalised. Reimbursement has been awarded to the 

majority of orphan drugs (22 out of 26 drugs). Table 9.2 in annex summarises 

reimbursement dossiers of all 26 drugs. Some of these have been re-submitted at a later 

date. 

The DRC’s advice was positive for 19 drugs. All these were approved by the Minister of 

Social Affairs. 

For one drug, there was no advice from the DRC, as no consensus could be reached. 

This drug was approved by the Minster of Social Affairs 

Two out of the six drugs for which the DRC’s advice was negative, were granted 

reimbursement by the Minister. 

For two of these three drugs it appears from the dossiers that both the DRC and the 

pharmaceutical company proposed a number of elements for negotiation - including a 

price decrease, employment opportunities, restrictions on the size of the patient 

population, the funding of diagnostic tests by the company, a reduction of the dosage - 

which may have played a role in awarding reimbursement. 

In the case of the third orphan drug, EMEA had granted an initial conditional marketing 

authorisation subject to the condition that the pharmaceutical company carried out 

additional clinical studies and submitted a new registration application to EMEA. In 

Belgium, reimbursement was granted to this drug, even though the DRC noted that 

there was insufficient evidence of the effectiveness of the drug in daily clinical practice 

and in the long-term. Following a new registration application, the DRC will revisit the 

reimbursement application. The provisional award of reimbursement in return for an 

engagement to undertake further clinical research amounts to a public subsidy for 

clinical research. It could be argued that this creates an uneven playing field for clinical 

research between pharmaceutical companies. 

The rationale for not granting reimbursement to four orphan drugs may be related to 

the high cost of the orphan drug in comparison with alternative drugs or the existence 

of other non-orphan indications of the drug. 

Using the first level of the ATC drug classification system, orphan drugs mainly related 

to ‘L Antineoplastic and immunomodulating agents’ (10 drugs) and ‘A Alimentary tract 

and metabolism’ (9 drugs); but also included ‘C Cardiovascular system’ (2 drugs); ‘V 

Various’ (2 drugs); ‘G Genitor-urinary system and sex hormones’ (1 drug); ‘H Systemic 

hormonal preparations, excluding sex hormones and insulins’ (1 drug); and ‘N Nervous 

system’ (1 drug). 

The evidence of therapeutic value included in the reimbursement dossier was similar to 

the evidence submitted to EMEA for registration purposes. This may reflect the short 

time period (an average of 130 days according to NIHDI/INAMI data) between EMEA 

registration approval and submission of the reimbursement application to the DRC in 

Belgium. The reimbursement dossier of one orphan drug included an additional clinical 

study that had not been available at the time of registration with EMEA.


In general, the evidence of therapeutic value was limited, with evidence derived from 

few clinical studies. 

The methodological design of studies varied considerably, with clinical evidence derived 

from double-blind randomised controlled trials, open-label studies and case series. Ten 

dossiers included clinical evidence from double-blind randomised controlled trials for 

orphan drugs relating to various ATC drug classes including ‘A Alimentary tract and 

metabolism’, ‘C Cardiovascular system’, ‘G Genitor-urinary system and sex hormones’, 

‘L Antineoplastic and immunomodulating agents’ and ‘G Genitor-urinary system and sex 

hormones’. Clinical studies of 13 orphan drugs had been published in peer-reviewed 

journals. 

Orphan drugs were positioned as first-line treatment (11 drugs) or second-line 

treatment (10 drugs) or both (4 drugs). There appears to be a therapeutic need for 

some orphan drugs in the absence of alternative treatments. However, alternative 

treatments were available for 15 orphan drugs. In this respect, it should be noted that 

some orphan drugs shared common indications, i.e. Nexavar ® and Sutent ® for advanced 

renal cell carcinoma; Fabrazyme ® and Replagal ® for Fabry disease; Revatio ® , Tracleer ® 

and Thelin ® for pulmonary arterial hypertension; Glivec ® , Sprycel ® and Tasigna ® for 

chronic myeloid leukaemia; Ceplene ® , Revlimid ® and Thalidomide ® for multiple 

myelome. 

In the absence of Belgian methodological guidelines to conduct a budget impact analysis, 

analyses included in reimbursement dossiers were generally simplistic. The number of 

patients and drug market share in Belgium were estimated or assumed by the 

pharmaceutical company. Budget impact analyses considered drug reimbursement tariffs 

rather than public prices. No dossier took into account the fact that the potential 

reimbursement of the orphan drug is likely to influence the market share of and the 

number of patients using alternative drugs or treatments. Potential savings are nearly 

never mentioned. Analyses were limited to examining the impact of drug costs and did 

not consider total treatment costs. One can assume this is not done as the cost of the 

drug is dominant in the treatment cost, and other costs like consultations or tests, are 

marginal in comparison. 

In general, reimbursement was sought in Belgium for the indication registered with 

EMEA. For three drugs, a reimbursement application was submitted for one of two 

indications registered with EMEA. If a pharmaceutical company submits multiple 

reimbursement dossiers relating to different indications of the orphan drug rather than 

one dossier relating to all indications, the DRC assesses the budgetary impact for an 

individual indication, but is not able to assess the total budgetary impact spanning all 

indications of the orphan drug. 

Key points 

• Reimbursement is awarded to the majority of orphan drugs. 

• In addition to the official criteria used by the DRC, other arguments such as 

price, employment, patient population, funding of diagnostic tests by the 

company may play a role in the reimbursement decision of the Minister. 

• The provisional award of reimbursement to one orphan drug in return for 

an engagement to undertake further clinical research in effect amounts to a 

public subsidy for clinical research. 

• Decisions of not granting reimbursement to some orphan drugs were 

related to the high cost of the orphan drug in comparison with alternative 

drugs or the existence of other non-orphan indications of the drug. 

• It is possible to derive evidence of therapeutic value from double-blinded 

randomized controlled trials. 

• There appears to be a therapeutic need for some orphan drugs in the 

absence of alternative treatments. 

• Budget impact analyses were simplistic and there is a need for principles of 

good practice for budget impact analyses.


• The DRC needs to consider the total budget impact of successive 

reimbursement dossiers of an orphan drug relating to different indications. 

5.4 IN-DEPTH ANALYSIS OF 15 SELECTED REIMBURSEMENT 

DOSSIERS 

5.4.1 Comparison of the evaluations by EMEA 

5.4.1.1 Objective 

One of the objectives of the KCE project was to document the different steps leading 

to approval and reimbursement of orphan drugs in Belgium. The data on which 

decisions are based, are provided to EMEA by the company in the form of a Marketing 

Authorisation application file (Common Technical Dossier, CTD). If regulatory approval 

is obtained a European Public Assessment Report (EPAR) and the Summary of Product 

Characteristics (SPC) are made public by EMEA. In order to obtain reimbursement for 

the approved drug the company provides data to the Belgian agency deciding on 

reimbursement (NIHDI). 

In order to get a feeling for the possible redundancy of the local evaluation it was 

checked whether the same study data sets were provided to EMEA and NIHDI, and 

whether the EPAR could be considered an alternative for the local evaluation (and if not 

how, it could be improved to also serve this purpose). 

5.4.1.2 Methodology 

First, a list of EMEA approved orphan drug indications was compiled based on either 

cases selected for the KCE study or recent approvals. The approval could be under 

exceptional circumstances or not. The list is given in annex 8.6. 

For each drug we focused on the first EMEA approval of orphan indication(s). We 

focused on clinical efficacy and only on the primary endpoint. This is a limitation of the 

study. Evaluating benefits and risks of an orphan drug in a specific indication involves 

much more than just looking at a primary endpoint. However the primary endpoint has 

the advantage that the method of analysis is (or should be) pre-defined in the study 

protocol and the statistical analysis plan of the sponsor. 

In case Marketing Authorisation had been granted under exceptional circumstances 

without study and demonstration of benefit based on clinical endpoints, the CHMP 

requested phase 4 clinical trial was considered instead, which was performed in order 

to obtain a normal Marketing Authorisation. 

The pivotal clinical efficacy trials were identified and their pre-defined primary endpoint, 

as well as the result obtained. These steps were followed separately for the three data 

sources and compared. 

1. The Marketing Authorisation application file (common technical document 

(CTD part 2 (2.7.3), clinical summary which include the clinical summary or 

expert report, tabular formats, study synopsis (the full ICH study reports 

were not checked). 

2. The European Public Assessment Report (EPAR) and the SPC. 

3. The file submitted by the company to the Belgian NIDHI for obtaining 


Data sources 1 and 2 were compared first. The CTD part 2.7.3 of the EMEA Marketing 

Authorisation application file was made available for review during a visit at EMEA in 

FEB 2009, under confidentiality. The EPAR reflecting the first orphan indication approval 

was in most cases available from the EMEA website or was made available for review 

during a visit at EMEA in FEB 2009, under confidentiality.


5.4.1.3 Results for comparison of CTD part 2.7.3 and EPAR 

In all of the 15 drug-indication pairs reviewed we identified the same pivotal trials and in 

most cases no differences were seen for the primary endpoint results between the 

CTD part 2.7.3 and the EPAR/SPC. 

As these are orphan drugs, for the vast majority of the 15 cases there is only a single 

pivotal trial with clinical endpoints. 

In two out of the 15 cases the results of the main statistical test as pre-defined in the 

study protocol for analysis of the primary endpoint was not mentioned in the 

EPAR/SPC, but instead only the result of an alternative statistical method was taken 

forward by the assessors and communicated as a measure of risk reduction. In both 

cases the effect of treatment using the pre-defined main statistical method was not 

significant. In both cases the alternative statistical method provided a p-value that was 

smaller than the prospective analytic method, and was numerically less than 0.05 in one 

case. The meaning of such alternative analyses is uncertain, given both the post-hoc 

nature and the multiplicity of analyses. It must be stated that these observations refer to 

a period in time when no templates were in use for the CHMP assessment report. 

Structure and level of detail was left to the discretion of the rapporteurs. In 2002, and 

following a major revision in 2004, the CHMP has adopted new templates for the 

assessment reports, including detailed guidance and structure in line with internationally 

agreed standards of scientific publications based on the CONSORT statement (The 

Lancet 2001; 357: 1191-94). Such templates are currently in use throughout the 

scientific assessment and have improved the assessment reports. 

In case of ongoing trials, the differences between the CTD and the EPAR in results for 

the primary efficacy variables was explained by additional information (more patients, 

longer follow-up) which became available at EMEA during that part of the review 

process which ends with drug approval and publication of the EPAR. This additional 

information was on file at EMEA but was not available for verification during the EMEA 

visit. An additional visit for checking these items was not considered necessary by KCE. 

In case results of new studies are provided by the applicant after publication of the first 

EPAR it is not always possible to find the results for the primary endpoint at the EMEA 

website. This observation is in agreement with EMEA policies: only certain types of 

variations trigger a revision of the EPAR, such as variations of the therapeutic indication. 

5.4.2 Comparison of the studies mentioned in the NIHDI file, the EMEA file 

and EPAR 

A comparison has been made between the primary endpoints of studies mentioned in 

the NIHDI file (being the company’s application sent to NIHDI), the company’s 

application sent to EMEA and the information contained in the EPAR. This comparison 

was performed for fourteen orphan drugs and fifteen indications. 

• In six cases the information provided in all three documents was the 

same. 

• One NIHDI file only contained the main study, not the supportive nor the 

extension study. 

• In two cases, the NIHDI file contains fewer studies than the EMEA file and 

EPAR. For the first drug, of the two studies contained in the EMEA file 

and EPAR, the study phase I/II is not mentioned in the NIHDI file. As for 

the other study, no numbers are given but the explanation is in line with 

the one of the EPAR. For the second drug, one phase II study with a 

primary endpoint of p=0.42 is not mentioned. 

• In one case the two studies of the NIHDI file correspond to the studies in 

the EMEA file and the EPAR. Nevertheless, the results of the second 

study are taken from the SPC (Summary of Product Characteristics) 

produced by EMEA. A negative study listed in the EMEA file is not 

mentioned in the NIHDI file.


• In one case the NIHDI file does not give figures, but explains the results, 

corresponding to the figures in the EMEA file and EPAR. 

• Two NIHDI files contain one additional study compared to the EMEA file 

and EPAR. This can be explained by the fact that the study started after or 

that the study’s first results were published after the EMEA procedure 

ended. 

• For one orphan drug, the studies are the same in all documents, but the 

results differ. This can be due to the fact that the study covered a long 

time-period and that results were measured at several times. 

• In one case the NIHDI file concludes the study showed a positive effect, 

while the EPAR states that “the data are too limited to conclude on the 

appropriate dosing in children”. 

In general, it can be said that the sponsor’s application files sent to NIHDI contain 

similar but not always the same data as the ones provided to EMEA and to be found in 

the EPAR. Differences are, when they occur, relatively small, although it is observed that 

if they occur, they are always to the advantage of the product. It is uncertain whether 

this has had an impact on the reimbursement decisions. 

Key points 

• In most cases, no differences were seen between the CTD part 2.7.3. and the 

EPAR/SPC in terms of primary endpoint results. 

• In two cases, an alternative statistical method was reported in the 

EPAR/SPC than the statistical test pre-defined in the study protocol. 

• In case of ongoing trials, differences between CTD and EPAR could be 

explained by additional information becoming available during the review 

process. 

• Generally, the companies’ drug reimbursement request files sent to NIHDI 

contained similar but not always identical information as the ones provided 

to EMEA and to be found in the EPAR. Small differences observed were 

always to the advantage of the product.


6 BUDGET IMPACT ANALYSIS 


The budget impact analysis of the orphan drugs on the Belgian health care budget is 

performed based on the situation at the end of 2008. 

The analysis is split into two parts: 

• an estimate of the budget impact at the end of 2008 in Belgium; 

• the development and application of scenarios for the future to estimate 

budget impacts in the short and medium term. 

The estimate at the end of 2008 has been done combining all potential information 

sources which is described in section 6.2 below. Most of these sources provide partial 

information which leaves a high level of uncertainty. 

Forecasts are based on scenarios that are described in section 6.3. The starting point 

for these forecasts is the estimate made for 2008. 

6.2 BUDGET IMPACT IN BELGIUM AT THE END OF 2008 

At the end of 2008, 31 different orphan drugs were approved for reimbursement in 

Belgium (of which 30 since 2003 when the Belgian orphan drug legislation was 

implemented). These 31 drugs correspond to 35 different indications. 

Figure 6.1 : Number of orphan drugs reimbursed per year in Belgium 

Approved in: 

1999 1 

2003 1 

2004 6 

2005 3 

2006 2 

2007 7 

2008 11 

Total orphan drugs 31 

More than half of the 31 drugs were approved in the last 24 months.


Figure 6.2 : Number of orphan drugs reimbursed per year and total over the 

years 1999-2008 in Belgium 

12 

10 

8 

6 

4 

2 

0 

1999 2003 2004 2005 2006 2007 2008 

Number of Orphan Drugs per year Total Orphan Drugs 

Figure 6.3 provides an estimate of the budget impact for all drugs approved by the end 

of 2008. 

These estimates are tentative, given the high degree of uncertainty of some variables. 

The reality lies probably in a bracket from -30 % of the calculated estimate to +30 %. 

For 2008, the real budget impact can therefore be located between 50 and 85 million 

Euro. 

The first source of information is the Ministerial Decree which always includes an 

estimate of budget impact. This published information 102 is based on the original file 

submitted by the sponsor to obtain reimbursement. The estimate made by the industry 

is always reviewed during the approval process, and sometimes a new (different) 

estimate is made by the DRC. 

The estimates provided in the Ministerial Decree are based on assumptions regarding 

some variables and are thus uncertain: 

• The number of patients is unknown, and simply applying the prevalence 

figures systematically leads to overestimates because not all patients will 

be treated. 

• In most cases, some time is needed to actually identify patients who may 

use the drug: the uptake of the medicine takes time (a few years). 

• Not all patients actually consume the doses as defined by the industry. 

There can be various reasons for this, but in practice, this will lead to a 

lower budget impact than forecasted. 

35 

30 

25 

20 

15 

10 

5 

0


Various other sources were used to make the estimate and cross-check: 

• Figures published by the NIHDI based on their internal information. These 

figures were made public at a hearing at the Federal Parliament in 

February 2009 and are also part of the MORSE report. 103 These include 

the number of patients that filed a demand to “colleges” for approval of 


• Figures available at the FPS Economy. The FPS Economy is in charge of 

approving pricing, and collects on a yearly basis the turnover information 

directly from the industry. The information obtained covered 2007 and 

was for a relatively small number of drugs. 

• Revision files: various drugs had to submit files for revisions, whether as a 

planned revision for drugs having been more than three years on the 

market, or because they asked for an extension (e.g. a new dose). These 

files and the published Ministerial Decrees, include more recent 

information on the budget impact than was available in the original files. 

• Information from the SSF: the SSF is used to obtain reimbursement for 

individual patients between the Marketing Authorisation and the 

reimbursement decision by the CTG. 

• IMS figures. 

All estimates are based on a calculation based on the number of patients (linked to the 

prevalence) and the average cost of a treatment of a patient. The table below therefore 

includes the information on prevalence, number of patients and average cost. A scoring 

was also included as to the reliability of the estimate: 

• Score A = both the number of patients and the average cost can be 

considered as fairly reliable estimates; 

• Score B = either the number of patients or the average cost can be 

considered as highly uncertain; 

• Score C = both the number of patients and the average cost can be 

considered as uncertain. 

This estimate should be considered as an operational exercise rather than scientific as it 

combines different types of information sources: forecasts for the drugs recently 

launched and real figures for drugs that are longer on the market.

Orphan drug 


Figure 6.3 : Overview of the estimated budget impact of orphan drugs in 

Belgium 

Reimbursed since 

Nature of disease 

(O= oncological, NO 

= not oncological) 

Number of Patients 

treated 

Cost/patient / year in 

000 € 

Total estimated cost 

to budget 2008 in 000 

€ 

Aldurazyme® 1/8/04 NO 9 312 3,600 A 

Atriance® 1/6/08 O 24 23 / adult; 14 

/ child 

Reliability of estimate 

160 B 

Busilvex® 1/10/08 NO ~44 4.6 205 B 

Carbaglu® 1/9/06 NO 14 -1 085 1,106 A 

Duodopa® 1/3/07 NO 73 49 4,000 A 

Elaprase® 1/1/08 NO 8 300 1,600 B 

Evoltra® 1/7/08 O ~10 64 200 C 

Exjade® 1/8/07 NO ~1 080 Varies 3,000 B 

Fabrazyme® 1/8/04 NO 48 195 7,500 A 

Glivec® As drug cat 2 

(1/7/2003) 

O 120 31- 48 4,800 A 

Increlex® 1/8/08 NO 1 40 40 A 

Lysodren® 1/1/08 O 36 6.5 167 C 

Myozyme® 1/5/07 NO 23-33 176 / child; 411 / 

for adult 

7,800 B 

Naglazyme® 1/12/08 NO 0 376 0 A 

Nexavar® 1/4/07 O 215 24 weeks: 15 

30 weeks: 19 

52 weeks: 33 

3,700 B 

Orfadin® 1/7/06 NO 14 50 -100 1,200 B 

Replagal® 1/8/04 NO Cost already counted in Fabrazyme B 

Revatio® 1/6/07 NO 70-142 7 - 26 1,500 B 

Revlimid® 1/4/08 O 60 5,500 B 

Savene® 1/9/07 NO 29 10 150 C 

Somavert® 1/4/04 NO 70 per year 1,600 C 

Sprycel® 1/9/07 O 85-900 4,800 B 

Sutent® 1/4/07 O GIST: 73 

mRCC: 180- 

240 

GIST: 6 

mRCC: 21 

3,000 C 

Tasigna® 1/9/08 O Cost counted with Sprycel B 

Thelin® 1/1/08 NO 50 32 3,900 A 

Torisel® 1/12/08 O 0 30 0 A 

Tracleer® 1/8/04 NO 358 37 4,700 B 

Trisenox® 1/11/05 O 4 37 275 A 

Xagrid® 1/11/05 NO 320 7 1,500 A 

Zavesca® 1/9/05 NO 2 93 200 A 

TOTAL 66,203


Comments regarding this estimated budget impact: 

• One orphan drug has not been included because of absence of 

information (Thalidomide®). 

• The estimated cost is only the cost of the drug, not of the total 

treatment. 

• Savings are not taken into account. For orphan drugs in the category “no 

alternative”, the potential saving is linked to treatment of symptoms of the 

disease. For orphan drugs in the category “significant benefit”, the saving 

is the alternative treatment. 

• The costs of the orphan drugs reimbursed through the SSF are not 

included in the table above, as they are not yet known for 2008 and cover 

orphan drugs that are not part of the “official list” of reimbursed drugs. 

(The SSF reimbursing only drugs not (yet) reimbursed under the normal 

scheme). For 2007, this cost was near to € 4 million, but one drug 

(Myozyme®) accounted for € 3.5 million. 

The total estimated cost to the NIHDI budget of € 66.2 million corresponds to more 

than 5 % of total hospital drugs budgets in 2008. 

6.3 BUDGET IMPACT FORECAST 

Three scenarios are applied to estimate the future budget impact: a conservative 

scenario (low growth/cost), a realistic scenario (best estimate) and a higher growth/cost 

scenario. 

These scenarios are based on following variables: 

• An estimate of the average number per year of orphan drugs that will 

obtain a Marketing Authorisation at the European level. 

• An estimate of the number of drugs per year that will obtain a positive 

reimbursement decision in Belgium. 

• The average cost per patient per year per drug. 

The applied estimate of the average number of orphan drugs that obtain a Marketing 

Authorisation is based on the past. At the end of 2008, 48 orphan drugs had obtained a 

Marketing Authorisation (Figure 6.4.). 

Forecasting the number of Marketing Authorisations can be based on the evolution of 

the number of Orphan Drug Designations granted by the EC.


Number of approved MA per year 

Figure 6.4 : Number of approved Marketing Authorisations per year and 

total number of Marketing Authorisations over the years 2001-2008 

14 

12 

10 

8 

6 

4 

2 

0 

2001 2002 2003 2004 2005 2006 2007 2008 

Number of approved MA per year Total number of MA per year 

[Source]: DG Enterprise EC. Register of designated Orphan Medicinal Products. 

. 11/3/2009. 

The figure below gives an overview of this evolution over the years since the legislation 

on orphan drugs exists. 

Figure 6.5 : Overview of Orphan Designations 2000-2008 

Year Applications 

submitted 

Positive 

COMP 

Opinions 

Applications 

withdrawn 

Final negative 

COMP Opinions 

60 

50 

40 

30 

20 

10 

0 

Total number of MA per year 

Designations 

granted by the 

Commission 

2008 119 86 31 1 73 

2007 125 97 19 1 98 

2006 104 81 20 2 80 

2005 118 88 30 0 88 

2004 108 75 22 4 72 

2003 87 54 41 1 55 

2002 80 43 30 3 49 

2001 83 64 27 1 64 

2000 72 26 6 0 14 

Total 896 614 226 13 593 

[Source]: Committee for Orphan Medicinal Products. January 2009 Plenary Meeting, Monthly 

Report. EMEA. Doc. Ref.: EMEA/COMP/694107/2008. 7 January 2009. Available from 

[Last accessed: 10/3/2009].


A total of 593 designations were granted by the end of 2008. 

Both the designations and the Marketing Authorisations seem to have reached a “cruise 

speed”, also in comparison with the situation in the USA. The estimate is therefore that 

there will be an average increase of at least 10 drugs per year. This figure also 

corresponds to expert opinions and the expectation from EMEA. There are no signs at 

this stage that drugs might be taken off the market. This can however be expected to 

happen in the longer term, for example when new therapies are introduced that replace 

existing orphan drugs. This has not been taken into account in the forecast as it 

probably will not have a significant effect in the next five years. 

• Realistic scenario: net increase of 10 new orphan drugs / year 

• Low growth scenario: net increase of 8 orphan drugs per year 

• High growth scenario: net increase of 12 orphan drugs per year 

Most of the orphan drugs that obtain a Marketing Authorisation are getting (after a 

delay) a positive reimbursement decision in Belgium. This has been the experience up to 

now, and therefore a transfer ratio of 90 % (9 out of 10 orphan drugs) has obtained a 

positive reimbursement decision in Belgium. This is valid for all the scenarios. 

• Realistic scenario: transfer ratio of 90 % 

• Low growth scenario: transfer ratio of 80 % 

• High growth scenario: transfer ratio of 100 % 

The average cost of a reimbursed drug over 2008 is estimated at € 2.135 million Euro. 

This is much higher than in 2007 when it was 1.6 million. The average of € 2.135 million 

is probably too low, as more than one in three orphan drugs were approved during 

2008, and were introduced in the course of the year. Their budget impact will be higher 

in 2009. The € 2.135 million is on the other hand a high average, as it is influenced by a 

few drugs with a high budget impact. Many drugs are expected to have budget impacts 

well below that average. 

• Realistic scenario: average cost of € 2.135 million / drug / year 

• Low growth/cost scenario: average cost of € 2.0 million Euro / drug / year 

• High growth/cost scenario: average cost of € 2.3 million Euro / drug / year 

The chart below gives the results of the application of these scenarios, starting from a 

budget impact estimate of € 66 million for 2008. The SSF cost is not included. The 

application of the realistic scenario would lead to a budget impact of € 162 million in 

2013 or an increase of 145 % over 5 years. Although it is (also) difficult to estimate the 

total cost of drugs to the budget in five years, this amount should represent close to 2 

% of the total cost of drugs to the budget and over 10 % of the total drugs cost of 

hospitals. 

This growth forecast is slower than the recent past, as based on an increase of 100 % 

between 2007 and 2008 (with an increase of 50 % in the number of reimbursed orphan 

drugs) and the estimated increase in the MORSE report 103 of the NIHDI was 50 % 

between 2007 and 2008 (that estimate covered only the 18 drugs with a college). 

The same restrictions that apply on the budget estimate for 2008 apply for the forecast: 

• the basis for this forecast is the estimate for 2008 which combines forecasts 

and actual costs; 

• the parameters used for the forecasts add to the uncertainty factor.


250 

200 

150 

100 

Figure 6.6 : Estimation of budget impact according to three scenario’s 

50 

0 

Key points 

2008 2009 2010 2011 2012 2013 

realistic 

• For 2008, the budget impact of orphan drugs in Belgium was estimated to 

range from 50 to 85 million Euro, which corresponds to over 5% of total 

hospital drugs budgets. 

• Three scenarios were applied to estimate the future budget impact: a 

conservative scenario (low growth/cost), a realistic scenario (best estimate) 

and a higher growth/cost scenario. 

• It was estimated that 10 new orphan drugs would reach market each year. 

• It was assumed that 90% of orphan drugs would gain reimbursement in 

Belgium. 

• It was estimated that the average cost of a reimbursed orphan drug would 

amount to 2.135 million Euro per year. 

• The realistic scenario would lead to a budget impact of orphan drugs of € 

162 million in 2013 or an increase of 145 % over 5 years. This would 

represent close to 4% of the cost of all drug reimbursements to the budget 

and over 10 % of total drugs costs of hospitals. 

Low 

High


7 DISCUSSION AND CONCLUSIONS 

7.1 ORPHAN DRUG DESIGNATION AS A TACTICAL STEP 

One of the criticisms of the present system of Orphan Designation is that it allows 

medicinal products for ‘normal’ diseases to be designated as orphan drugs. 

This can happen when drugs are developed for a specific type of patients/disease (a 

practice called “targeting”), or when one disease is split into various sub-categories each 

presented with its own characteristics, a practice called “sub-setting” which is 

described above in the report (chapter 3): 

Sub-setting can lead to so-called “salami-slicing”: this is creating artificial subsets of a nonorphan 

condition, and basing the prevalence criterion on an unreal subpopulation. The aim is to 

obtain market exclusivity, a decrease of the costs and obligations linked to the registration 

demand, and an increase of the exclusivity through new subpopulations (also known as the 

“evergreening tactic”). 

The industry is suspected of playing it tactically by introducing drugs to the market as 

‘orphan’, to fully reap the advantages (incentives) offered for the development of a drug 

with Orphan Designation, and then at a later stage to increase the number of 

indications for the same drug. This risk factor is increased by the fact that many 

oncological drugs obtain the orphan designation. As of today, one third of the orphan 

drugs on the Belgian market are for oncology, and their budget impact is also 

approximately one third of the budget impact of all orphan drugs. 

The COMP is very critical about the use of these techniques and adapts its own practice 

accordingly. Sub-setting is allowed under conditions. However, it seems impossible to 

exclude completely the possibility that manufacturers turn once orphan drugs into 

commercially highly profitable products later on. 

7.2 PREVALENCE VERSUS ECONOMIC MOTIVES 

As set out in Chapter three of this report, legislation on Orphan Designation at the EU 

level calls on two main criteria to decide on designation: either the (low) prevalence, or 

the high investment needed compared to the potential income. 

Both have the same underlying reasoning and are essentially considered to mean the 

same: a (very) low prevalence was for the legislator the equivalent to high investments 

for a potentially small market. The fact that both criteria are formulated as “either / or” 

instead of “and” has however some consequences. 

Nearly all designations are granted based on prevalence. Only one designation was 

granted based on low ‘return on investment’: an Orphan Designation for a tropical 

neglected disease tt (tuberculosis) - not a rare disease. Only five demands were filed 

based on the return on investment criterion. With only one approval this means a very 

low success rate compared to the other criterion. 

Although judging the economic criteria is objectively speaking not particularly difficult, it 

faces a number of barriers: those who have to make the judgement have usually been 

trained in the field of health and do not have an economic background (hence lack the 

expertise) and the industry uses the argument that it is not possible to allocate costs 

clearly to one drug. 

This situation has become an issue that requires attention for the following reasons: 

• the high prices asked for orphan drugs raise the question to what extent 

these are indeed a fair reflection of the costs incurred by the industry – 

or rather just generate high profits for the industry; 

tt Interview with Dr. Jordi Llinares, EMEA, on the 14th of November 2008.


• it has been demonstrated uu that a few cases of orphan drugs which 

obviously required a very low level of investments have been brought to 

the market. 

Some orphan drugs generate revenues of hundreds of millions Euro per year. These are 

not yet “blockbusters” but these drugs obviously have reimbursed their initial 

investments and generate a high level of return to the sponsor. The legislator has 

foreseen the possibility to withdraw the market exclusivity after five years. This can be 

done at the initiative of an EU Member State. Yet, this has never happened up to now, 

and it seems unlikely that any individual Member State will take this initiative. The main 

reason why this is unlikely to happen is the absence of an agreement on what would be 

an acceptable return on investment. 

The overview below presents the trade-off between both interpretations of the 

legislation in terms of advantages and disadvantages. 

“either / or” “and” 

Advantages Stimulates innovation because less Would improve the application of 

barriers for industry 

the ‘spirit’ of the legislation 

Disadvantages Non-innovative, low investment Threshold for industry would be 

drugs can obtain orphan designation higher 

An adaptation of the legislation to “and” would potentially delay patient access to new 

drugs because two new barriers for the development of orphan drugs compared to the 

present situation would be created: 

• the need for industry to provide evidence (more work); 

• the need for COMP to evaluate based on economic criteria (need for 

additional expertise). 

7.3 ASSESSING CLINICAL ADDED VALUE 

Assessing the clinical added value of orphan drugs is a challenge essentially because of 

the low number of patients. The techniques and standards used for drugs in general to 

confirm clinical effectiveness are difficult to apply on orphan drugs. 

At EMEA level, the clinical effectiveness is checked at the moment of deciding on 

Marketing Authorisation. Although the process is identical for orphan drugs compared 

to non-orphan drugs, there are guidelines that relate to clinical trials in small 

populations 32 . 

The clinical added value is assessed first by the CHMP as part of the Marketing 

Authorisation process and a second time at the national level for reimbursement. The 

same limited information is used. The decision for market access is taken on absolute 

grounds (the drug is authorised to go to the market or not), the decision for 

reimbursement on relative grounds (‘given the alternatives, this drug is worthwhile to 

be reimbursed”). 

At both decision levels, the analysis for orphans and for non-orphan drugs is done by 

the same organisations and based on the same criteria. 

Considering the clinical added value, most positive decisions taken by the CHMP to 

grant access to the market are based on a ‘benefit of the doubt’. For orphan drugs, 

there is seldom proof of clinical added value at that moment. 

The comparison that was performed between the work undertaken at EU level and at 

national level in Belgium confirms that both analyses are based on nearly identical 

information (see chapter 3 and 4). 

uu See the discussion of the ‘pricing issue’ in this chapter.


Even if the decisions to be taken on the basis of the same information are different, 

there are obvious efficiency gains to be achieved. 

The EMEA decision process is more efficient compared to 27 individual national 

analyses for deciding on reimbursement. The work is actually done by two national 

Member States agencies, and a common opinion and decision is reached among all 27 

Member States at the CHMP. Creating a similar system specifically for the assessment of 

clinical added value and serving as input in the national decision regarding 

reimbursement at EU level would seem a logical next step. 

This has been suggested already at two occasions: 

• Eurordis (European Organisation for Rare Diseases) 104 made a 

recommendation in this respect. This recommendation is motivated by 

the differences in speed of market access among Member States. Bringing 

this aspect to the EU level would speed up decisions in Member States 

and avoid the present inequalities (industry concentrating on market 

access in procedurally easier or larger Member States); 

• The Pharmaceutical Forum 105 proposes an exchange of knowledge among 

Member States and to start an early dialogue between pricing and 

reimbursement authorities. 

Another approach that is suggested (see chapter 2 above) is through the use of patient 

registries. An early patient registry, including data on the natural history of the rare 

disease and economically important variables, would allow regulatory authorities to 

follow up and evaluate long term continuous data collection and monitor the clinical 

efficacy over time. Setting up such patient registries is however a challenging task, as it 

would mean setting up a registry even before a drug is being developed. In practice it is 

uncertain for which rare disease a treatment will be developed. As the number of rare 

diseases is relatively high, questions about financing and governance of rare disease 

registries before the development of a treatment can be raised. 

An early patient registry, including data on the natural history of the disease and 

economically relevant parameters, would allow regulatory authorities to follow up and 

evaluate the uncertainties surrounding longer-term effectiveness and cost-effectiveness 

of an orphan drug in the relevant population. 25 Such an approach would support the 

decision-making process and allow more timely access to orphan drugs for patients. It 

would however not change the actual models on which decisions are based. 

The option to use disease and patient registries is described below. 

7.4 THE NEED FOR A RIGHT BALANCE BETWEEN ETHICAL 

AND ECONOMIC CONCERNS 

The development, marketing and reimbursement of orphan drugs challenge the general 

principles that underpin our current reimbursement policy. 

The average price of orphan drugs on the market today is high, which renders the 

current approach to orphan drugs potentially economically unsustainable. Moreover, it 

may be argued that it creates inequities because the life of one person is valued higher 

than the life of another. 22 This stretches the solidarity principle which underpins the 

health care system. 

The quote below from the conclusions of a NHS technology assessment study on 

Enzyme Replacement Therapy (ERT) for Fabry disease illustrates this situation: 

“Although ERT for treating the ‘average’ patient with Fabry’s disease exceeds the normal upper 

threshold for cost-effectiveness seen in NHS policy decisions by over sixfold, and the value for 

MPS1 is likely to be of a similar order of magnitude, clinicians and the manufacturers argue 

that, as the disease is classified as an under European Union legislation, it has special status, 

and the NHS has no option but to provide ERT. More information is required before the 

generalisability of the findings can be determined. Although data from the UK have been used 

wherever possible, this was very thin indeed.


Nonetheless, even large errors in assumptions made will not reduce the ICER to anywhere near 

the upper level of treatments usually considered cost-effective.” 106 

The perceived extent of this problem is exacerbated by the fact that the costeffectiveness 

of orphan drugs is not assessed in Belgium at the moment of the 

reimbursement decision - as it is considered that the information can never be 

sufficiently reliable due to the low number of patients. 

At the same time, fair distribution principles do not allow to exclude orphan drugs 

altogether from being reimbursed. Reimbursement of orphan drugs fit within the 

objectives of health care provision and fit within our system of social solidarity in which 

vulnerable groups receive support. 

And this may imply (limited) correction to market mechanisms. Furthermore, there is 

little support within the domain of social healthcare provision in general (in Belgium) for 

the application of a pure cost-effectiveness and efficiency reasoning. 22 

The tension that currently exists between different societal concerns regarding orphan 

drugs needs to be addressed. 

The current situation leads to individual persons following their own ‘common sense’. 

Those who have to take decisions in the decision-making chain, from reimbursement 

decision for the drug to individual patient’s eligibility, are confronted with this dilemma 

and potential inequity. Anecdotal evidence collected shows that this ’tension‘ can lead 

to decisions like patients being refused a therapy because of age although this is 

nowhere mentioned as a criterion. 

A first step towards a solution to this situation would be to initiate a societal dialogue 

on the issue, to clarify what society wants and accepts in terms of ethical and economic 

consequences. 

7.5 PRICING 

From a regulatory point of view, the pricing of orphan drugs is not different to other 

drugs. The market conditions are however different to normal drugs. 

Facts and background: 

• The price is not an issue when the decision on market access is taken 

(EMEA – Marketing Authorisation). 

• The price is defined by the industry and submitted for approval to national 

authorities. In Belgium this is to the FPS Economy, in a process that runs 

in parallel to the reimbursement decision. The result is the acceptance of 

a maximum price. The analysis performed by the FPS Economy is mainly 

based on comparisons. For orphan drugs, this means comparison with 

other countries. 

• Price negotiations are in principle not part of the drug reimbursement 

decision process. The price approved by the FPS Economy is considered 

to be the basis for reimbursement. 

• There is generally no negotiation on the price. The only negotiation that 

may occur is by the government, between the advice of the DRC and the 

actual (publication of the) decision. This is mainly linked to the budget 

impact and can lead to a compromise with the industry to get approval. 

Price could be an element in the negotiation, but in practice it is not. 

• The DRC could (re-)negotiate the price at regular revisions. This has 

however not yet happened for orphan drugs.


Small monopolies 

The price is an essential element of the context created by the orphan drug legislation. 

Drugs to treat rare diseases are considered as a small market, which has a number of 

implications: 

the investment for industry is high compared to the potential market size; 

the risks for the industry are high in terms of return on their investment. 

Legitimate concerns that these factors would discourage industry from developing 

orphan drugs have led to legislation which aims to reduce the risks, providing incentives 

for investments in research for rare diseases and for the market introduction of orphan 

drugs. This legislation has created a comfortable situation for the pharmaceutical 

industry: 

they obtain market exclusivity for orphan drugs (no direct competition); 

the price is set by the industry and is not negotiated by any party. 

The end result is that small ‘virtual monopolies’ are created in which the industry is free 

to ask the price they want for orphan drugs. These often high prices are justified by the 

need to reimburse the research and development costs. 

There are however no market mechanisms in place to correct a potentially too high 

price: 

• there is no direct or indirect competition, as is the case for other drugs; 

• customers have no bargaining power towards the industry; 

• the market is closed for competition: no competitor will run the risk to 

invest in an alternative medicinal product as the legislation blocks the 

(small) market access for ten years. 

As such, the legislation which has a favourable impact in terms of the supply of orphan 

drugs to the market has, through its distortion of the market mechanisms, also the 

adverse effect of too high prices not being adjusted. The current rules do not, however, 

preclude the production of generics or biosimilars for orphan drugs once the period of 

market exclusivity is passed. The production of generics or biosimilars may in the 

medium term reduce the prices of orphan drugs. 

Adding to the problem is the fact that the market for drugs in general and for orphans, 

is not transparent. Information on effectiveness and hence cost-effectiveness of the 

treatment is not available at the moment of market access, and is not available post 

Marketing Authorisation either. Information on clinical effectiveness is frequently (very) 

limited, as explained above, and decisions to grant market access are often taken 

allowing the ‘benefit of the doubt’. 

“Identical” medicines 

Three of the 48 orphan drugs with Marketing Authorisation at the European level are 

drugs that have a “twin” product on the market. These twins are for other, non orphan 

indications and have a different brand name. 

The orphan version of the twin is always marketed at a higher price. 

The best known example is Revatio® which is another name for Viagra®. The two 

other products are: 

• Savene® (orphan) being the same product as Cardioxane®. Savene® is 

sold in Belgium, Cardioxane® not. If it was available on the Belgian 

market, one can assume it would be prescribed instead of Savene® 

• Siklos® (orphan) is identical to Hydrea®: one is delivered as capsules, the 

other in the form of tablets. Siklos® is not on the Belgian market and one 

can assume that patients of well informed medical doctors are receiving 

Hydrea®.


In the example of Revatio® / Viagra®, both produced by the same company, the 

decision to develop a different brand for the orphan indication is almost certainly not 

motivated by a return on investment need. Rather, the orphan drug legislation provides 

an additional incentive for the industry to explore and introduce the drug in a specific 

market niche. Since investments are largely covered by the profits generated by Viagra, 

the ‘additional cost’ is essentially linked to clinical trials and to marketing. 

Compounding preparations 

Two orphan drugs that obtained a market authorisation from EMEA were refused 

reimbursement in Belgium because of the existence of an alternative in the form of a 

compounding preparation. 

Although both cannot be compared as one is an artisanal product and the other an 

industrial product, the price difference was such that it prevented approval. 

Conclusion 

The pricing issue is a key element of the equation. The orphan drug legislation creates a 

positive market environment through incentives, one of which is the creation of small 

virtual monopolies. Industry behaviour is to ask for high prices. Member States have 

little negotiation power and there are no market mechanisms in place to put a 

downward pressure on prices. 

The spirit of the legislation, being to stimulate research and development on drugs for 

diseases that would otherwise be neglected by industry and academia, is put at risk by 

this situation, as high prices also mean high budget impacts and in general low costeffectiveness 

in comparison to non-orphan drugs. 

Three potential routes to solve the existing problem are: 

• an adaptation of the legislation to ensure that its application happens 

more according to its spirit with analysis of the return on investment 

including subsidies received for R&D and justification of price setting; 

• the application of risk-sharing systems like price-for-performance schemes 

or conditional reimbursements 

• the organisation of price negotiations at the EU-level instead of at 

Member State level, which could be combined with both previous bullet 

points. 

Advantages and disadvantages of the first two are: 

Information on return on investment Risk sharing 

advantages • Is a logical consequence of the 

existing legislation, which should 

therefore be acceptable to all 

stakeholders 

disadvantages • This information needs to be 

assessed by experts 

• No need to provide information 

on investments and potential 

returns 

• Need to define performance 

criteria 

• Is a new technique, there is little 

experience with this type of pricesetting 

(in Belgium)


7.6 EXTENSION OF INDICATIONS 

Designation for an orphan drug is possible for indications with a prevalence up to 5 in 

10,000. 

In practice most orphan drugs are for ultra rare diseases, e.g.: 

Disease Prevalence Orphan drug 

Fabry disease 1.75 / 100,000 Fabrazyme® & Replagal® 

MPS I 1.3 / 100,000 Aldurazyme® 

MPS II 0.6 / 100,000 Elaprase® 

MPS IV 0.4 / 100,000 Naglazyme® 

Acute promyelocyctic leukemia 8 / 100,000 Trisenox® 

Chronic myeloid leukemia 6 / 100,000 Glivec® 

Cases exist where a drug obtained the designation and Marketing Authorisation for one 

indication, and then later this is extended to more indications. 

The legislation allows this. The same product can have more indications, and the 

prevalences for the various indications are not “added up”. 

Orphan drugs with more than one orphan indication at European and Belgian level are: 

Drug Number of indications EMEA Number of indications Belgium 

Glivec® 6 2 

Nexavar® 2 2 

Sprycel® 2 1 

Sutent® vv 2 2 

Tracleer® 2 2 

Changing the legislation to link the designation as orphan drug to the total prevalence of 

all indications would have consequences as described in the table below: 

Advantage Disadvantage 

Change the legislation • Would be more in line 

with spirit of legislation 

• Would ensure to 

concentrate on really 

rare 

• Would create a barrier 

to use the OD 

legislation for purposes 

it was not meant for 

vv Sutent® has withdrawn its orphan designation at EMEA level 

• Creates a 

potential barrier 

to develop new 

product-indication 

combinations


7.7 GROWTH OF THE BUDGET IMPACT OF ORPHAN DRUGS 

Total budgets for orphan drugs were very small when the legislation was launched in 

2000. 

Today they have become significant, even if the total number of patients treated is still 

limited. 

This high growth is powered by a number of factors: 

• the high average price of orphan drugs; 

• the steady increase in the number of orphan drugs coming to the market. 

In Belgium, there is no budget ceiling for orphan drugs, but the total cost of all drugs 

reimbursed does have a ceiling. When the global ceiling is reached, there are 

mechanisms to compensate for over-expenditure. The government can charge an 

alternative charge to the pharmaceutical industry to compensate 100% of the overexpenditure, 

with a maximum of €100 million per year. Orphan drugs do not contribute 

to this subsidiary charge. Orphan drugs as a group have no ceiling. 

The budget increase of orphan drugs therefore puts pressure on the total ceiling, and 

non orphan drugs industry is likely to pay for the orphan drugs industry. 

The cost of orphan drugs in Belgium is estimated to have been over 5 % of total hospital 

drug budgets in 2008 ww and further estimates indicate the future cost could be well 

above 10 % of hospital drug budgets in five years from now. Orphan drugs represent 

probably 2% of total drug reimbursement costs in 2009, and could represent close to 

4% in 2013. 

This high cost creates an upward pressure on health insurance budgets. If and when 

hundreds of orphan drugs become available, they would still cover only part of the 

needs of all the patients suffering from rare diseases. Moreover, relatively large amounts 

of the limited health care budget would go to a few patients, which may challenge the 

boundaries of solidarity. Based on the experience with a first set of 31 orphan drugs, 

the cost to the health insurance system under the present conditions could become 

unbearable. 

The high prices combined with the growing budget impact of orphan drugs also 

negatively affect the image of the orphan drugs among decision-makers. Globally 

speaking, the orphan drug legislation is considered by all parties to be a success. The 

price of this success is the rising budget. The negative image created puts the success at 

risk. 

7.8 VARIATIONS IN ACCESS AND USE AMONG MEMBER 

STATES 

Although the Marketing Authorisation decision grants access to the market in 27 

Member States, because of the cost of the drugs, effective access is reached only when 

the decision is taken to reimburse the medicinal product (at the national level). 

As a consequence, the effective market access and the utilization of orphan drugs vary 

among Member States. 

The situation of Belgium compared to other countries analysed can be summarised as 

follows: 

• Starting a process to decide on reimbursement of a drug is the initiative of 

industry. In practice, Belgium is not one of the countries that is chosen as 

a priority by industry. 

ww The number of individual patients treated is difficult to estimate both for orphan drug treatments and for 

hospital treatments, but one speaks of a difference in cost/treatment/patient that must be in the around 

one (for non orphan drugs) to one thousand (for orphan drugs).


• Out of the 47 orphan drugs having obtained Marketing Authorisation by 

end 2008, 31 are reimbursed in Belgium and 4 are not reimbursed. This 

puts Belgium at third place compared to France, Italy, the Netherlands 

and Sweden (see point 4.9). xx 

• The procedure to access reimbursement in Belgium takes in theory 180 

days, but will in practice, due to interruptions, last longer. There is little 

evidence that this process ends up to be much longer than in other 

Member States, but industry mentions this as the argument to be reticent 

to start reimbursement procedure. In comparison, an orphan drug having 

obtained Marketing Authorisation is automatically launched on the British 

market. But if the advice of NICE is requested for reimbursement, the 

procedure can be slow (see point 4.8). 

• In Belgium three systems exist for early access: the SSF, the medical needs 

programme and the compassionate use legislation (see 4.3.3.2 and 

4.3.3.3). The SSF de facto plays a role between Marketing Authorisation 

and reimbursement decision. It can be questioned if the SSF is an 

adequate mechanism for that purpose (awareness of patients and Medical 

Doctors, criteria, etc.). 

Early access (before Marketing Authorisation) 

In Belgium, early access is possible through the Special Solidarity Fund (see point 

4.3.3.3). 

Figure 7.1 : SSF reimbursement for Orphan Drugs with MA in 2007 

Orphan drug Total NIHDI Number of patients NIHDI expenditures 

Expenditures 

per patient 

Myozyme® € 3,540,723 7 € 505,818 

Revatio® € 299,358 € 67 € 4,468 

Revlimid® € 141,050 € 57 € 2,475 

Ventavis/Iloprost® € 100,927 € 9 € 11.214 

Tracleer® € 2,167 € 1 € 2,167 

Source: NIHDI. Jaarverslag 2007 betreffende het Bijzonder Solidariteitsfonds, 2008 

Several Member States have a particular procedure providing early access: 

• In France, orphan drugs can be accessed before they are reimbursed, 

through the ‘Authorisation for Temporary Use’ (ATU) procedure (see 

point 4.4). 

• A special fund for compassionate use was set up in Italy in order to 

finance early access to orphan drugs and trials on rare diseases (see point 

4.5). 

xx Information about the United Kingdom is not available.


7.9 AWARENESS RAISING 

Because of the low incidence of rare diseases, health professionals generally have a low 

awareness and little knowledge on how to treat such diseases. 

This explains the importance and focus of the EU level actions and national plans for 

rare diseases on: 

• developing awareness raising actions and tools; 

• developing tools to give access to knowledge and expertise including databases; 

• building expertise in specialized centres; for many Member States this 

implies to refer patients with a specific disease to a specific expert centre; 

• the added value of EU and international cooperation. 

The concept of “orphan drug” is a non-reality for the medical professionals. Their 

concern is the patient, the disease and the potential treatment. Whether the drug is an 

orphan drug or not has no importance. “Orphan drugs” is a technical concept, not 

understood, not commonly used by health professionals. 

Even for specialists on rare diseases and orphan drugs, there exists confusion on which 

drugs are “orphan” and which are not. Indeed, there exists a ‘grey zone’: 

• drugs for orphan indications that do not have the orphan status, either 

because they were introduced before the legislation, or because they are 

also used for non-orphan indications; some of these drugs do have the 

orphan status in the USA but (not yet) at EU level; 

• there is one drug that has the orphan status in Belgium but not at EU 

level yy ; 

• there are various drugs with orphan status at EU level or in the US, that 

are not reimbursed in Belgium; 

• etc. 

The only efficient solution to close this awareness gap seems to be to concentrate 

expertise. The route of setting up expert centres for rare diseases will also be beneficial 

for the promotion of therapies using the right orphan drug. 

7.10 COLLEGES AND CONTROL OF ELIGIBILITY 

In Belgium, orphan drugs can only be prescribed to individual patients if a number of 

conditions are met. These are defined by the DRC at the moment of the decision to put 

the drug on the list of reimbursed orphan drugs. Medical Doctors who wish to 

prescribe the drug have to ensure these conditions are met and confirm this when 

sending the application for the reimbursement to the health insurance organisations. 

In principle, this is linked to the control of the eligibility. It also serves to collect 

information that could be used later for revisions of decisions. 

In practice, the perception by Medical Doctors and the industry is that criteria and 

conditions (of which the relevance is not always clear) are added as a technique to 

create barriers to the use of orphan drugs. Examples are the need to renew the 

demand every six or twelve months for life-time diseases, or to repeat tests at regular 

intervals, which leads to (unnecessary) costs and a sometimes heavy physical and mental 

burden for the patient. This perception seems to be exacerbated by a lack of 

transparency and of return on the information provided. 

yy Duodopa®, which obtained the designation at national level in 2006; this would not be possible anymore 

today.


The Colleges of Orphan Drugs, when they exist, have the power to adapt and change 

these conditions, based on experience. This is apparently working, but is not done 

systematically or pro-actively although the Colleges do have a formal responsibility in 

this respect. It does put an additional burden and responsibility on the Colleges. 

The following observations can be made in relation to the functioning and the role of 

the Colleges: 

• the establishment of Colleges seems to be a good technique, as it allows 

to bring together the (rare) expertise; 

• the sickness funds are not legally required to ask the advice of the 

Colleges, but they nevertheless have a consensus to request it 

systematically; 

• the work volumes for these Colleges is very high, and the increase in the 

number of orphan drugs leads to the need to create a permanent support 

structure; 

• Colleges are reactive in their functioning; they do have a permanent 

structure but with little resources. With more resources, they could 

become more pro-active and propose changes and improvements; 

• their success raises the question as to what to do with the thirteen drugs 

out of 31 that have no College: should this not be systematic? ; 

• if a sickness fund takes a negative decision, it has the theoretical obligation 

to inform the College but there is little evidence that this leads to 

additional knowledge. If the Colleges reviewed all requests and registered 

systematically all decisions, both positive and negative, they would be in a 

better position to provide advice and information at the moment of 

revisions; 

• Colleges potentially pool a lot of information; it would be easy to ensure 

they concentrate all information. For the moment, the collected 

information is not easily available, e.g. the year reports are not publicly 

available. Making the information publicly available would improve the 

efficiency, also to decide on revisions. 

Typology of the Colleges: 

Total number of Colleges 18 

Therapeutic area Endocrinology/Metabolism: 10 

Neurology: 1 

Cardiovascular/respiratory: 3 

Oncology: 3 

Haematology: 1 

First or second line 11 First 

1 First/second 

6 Second 

Alternative? 9 have an alternative versus 9 

Treatment 8 peroral (by mouth) 

10 paranteral


7.11 USE OF REGISTRIES 

Patient or disease registries zz are used for various purposes and particularly in the case 

of rare diseases. Setting up patient and disease registries is part of the EU policy and is 

an action line in national rare disease plans that many Member States have or are setting 

up. 

Typical purposes why registries are being set up are: 

• to describe the natural history of a disease; 

• for research purposes (e.g. to have fast access to patients); 

• to determine clinical effectiveness; 

• to monitor cost-effectiveness; 

• to monitor safety and harm. 

Registries are set up for rare diseases before and independently of the fact a medicinal 

product is being developed. As there are an estimated 5,000 to 8,000 rare diseases, it is 

clear that registries exist for only part of the rare diseases. 

With regard to orphan drugs, there are two moments when registries are usually set 

up: 

• at the moment of Marketing Authorisation. The CHMP will on an ad hoc 

basis impose on the industry to set up a registry. This can be for various 

purposes mainly linked to the clinical effectiveness and/or the safety and 

harm monitoring; 

• at the moment of the decision on reimbursement, national authorities can 

also decide that setting up a registry is a condition for reimbursement. 

Each of these decisions is ad hoc, there is no standardisation, neither at EMEA level, nor 

at the level of individual Member States, nor among Member States. 

An exception is the MPS registry in the UK, that was set up before a drug for MPS was 

developed. 

The industry is in charge of funding and setting up these registries which goes against 

the important principle that data should be “independent” in the case of registries. They 

do this adequately but can decide autonomously on how and according to which 

standards it will be set up and managed nearly always by third parties. 

The existence of registries for the indications of orphan drugs is generally considered as 

an advantage offsetting the potential disadvantages (e.g. cost or privacy issues) and the 

difficulties linked to their management particularly to ensure their long term 

sustainability beyond the point in time where obligations for the EMEA are fulfilled. The 

main advantages are: 

• access to patients: both for research and market access (linked to the 

rarity); 

• transparency: it is a source of information for those who need to decide 

on the most adequate therapy (effective treatment); 

• control: it is a way for the reimbursement authorities to control whether 

the medicine is prescribed for the right type of patients, as well as to gain 

insights on whether the therapy is working and should be continued. 

zz Disease registry is a specially designed database with voluntary, observational clinical data collected 

from physicians and intended to explore and define the natural course and clinical characteristics of 

disease, as well as to track and characterize response to treatment. 

Patient register is a database (list) containing baseline information on the existence of patients with (a) 

certain disease(s), but without any longitudinal follow-up. 

(Working Group Pricing and Reimbursement. Improving access to orphan medicines for all affected EU 

citizens. The Pharmaceutical Forum. 2008. Available from 

[Last accessed: 10/12/2008].)


Willingness to participate in patient and disease registries is high among the medical 

professionals, which contrasts with their reluctance to provide a lot of information 

linked to the decisions for individual reimbursement. This difference is explained by the 

return for the Medical Doctor, which is real with a registry and most often absent for 

the latter. 

Transparency is an important value in the case of orphan drugs. Decisions on market 

authorisation are based on limited clinical evidence. Reimbursement decisions are based 

on the same limited clinical evidence, but are furthermore taken without information on 

cost-effectiveness. When the medicinal product is on the market, the normal market 

mechanisms are not working as there is no alternative to the treatment which is 

reinforced by the orphan drug legislation (market exclusivity). The transparency 

achieved through registries can compensate for this, especially by providing growing 

evidence on both the clinical effectiveness and the cost-effectiveness of the treatment. aaa 

Various routes exist to improve the use of registries in the case of orphan drugs: 

1. systematically setting up patient registries for all indications for which 

designations were granted; this will create value for all those involved later in 

the decision-making, including industry who will have easier access to 

patients, and for reimbursement authorities who can forecast the budget 

impact more precisely; 

2. standardizing the registries, at the EU level for clinical evidence; 

3. ensure coordination for aspects of clinical evidence between what is asked at 

EU level and what is asked at national level; 

4. systematically set up data collection on cost-effectiveness of treatments 

through registries; 

5. coordinate the cost-effectiveness information to be collected between 

Member States. 

This subject is worth a study on its own, but it is clear that value can be created 

through: 

• standardization and coordination between the various decision-makers; 

• collecting information on the effectiveness of the treatments / drugs after 

their introduction on the market. This will improve the quality of 

information available when revising reimbursement decisions; 

• transparency: it will allow the “market” to function better by ensuring the 

information flows. 

aaa An analysis based on the registry has however no added value for the assessment of the “incremental” 

cost-effectiveness of that respective drug, as such assessment requires a comparison with the “best 

alternative treatment”. Cost benefit can only be compared if data on the alternative treatment is available. 

A registry is (only) a way to monitor the effectiveness of a medicinal product.


Key points 

• The present system of Orphan Designation allows for medicinal products for 

‘normal’ diseases to be designated as orphan drugs. 

• The economic factors underlying Orphan Designation can be questioned in 

some cases as a low prevalence does not equal potential low return on 

investment. 

• Evidence about clinical added value of orphan drugs is rarely available at the 

moment of registration due to the low number of patients. European 

cooperation can lead to significant efficiency gains, particularly through the 

use of patient registries. 

• There is a need to find a right balance between ethical and economic 

concerns as this leads to tensions. A solution could be to initiate a societal 

dialogue on the issue, to clarify what society wants and accepts in terms of 

ethical and economic consequences 

• In essence, small monopolies are created to stimulate development and 

supply of orphan drugs, but there are no market mechanisms to adjust 

prices once drugs are on the market. 

• The growing impact of orphan drugs on the total budget for health 

insurance in Belgium is creating pressures. 

• Indications can be extended for an orphan drug and the total prevalence 

across indications is not considered. 

• Access of Belgian patients to orphan drugs in practice depends on the 

manufacturer submitting a reimbursement application and on the Drug 

Reimbursement Committee granting reimbursement. 

• Health professionals generally have a low awareness of rare diseases and 

orphan drugs due to their rare occurrence. 

• There is a need for a comprehensive approach towards defining and 

exercising the role of the Colleges of Orphan Drugs. 

• There is a need for a European standardised approach to setting up and 

using patient and disease registries. Centralisation will also increase the 

chances of long term sustainability.


8 APPENDICES


8.1 OVERVIEW REIMBURSED ORPHAN DRUGS IN BELGIUM 

Drug Indication Sponsor EMEA NIHDI 

Orphan 

Designation 

MA 

Submission 

date 

Approval 

date 

Reimbursed 

since 

Aldurazyme 

® 

Treatment of Mucopolysaccharidosis, type I Genzyme 14/2/2001 10/6/2003 26/6/2003 20/7/2004 1/8/2004 

Atriance® Acute lymphoblastic leukaemia GSK 16/6/2005 22/8/2007 19/9/2007 21/5/2008 1/6/2008 

Busilvex® Hematopoietic cell transplantation Pierre Fabre Medicament 29/12/2000 9/7/2003 7/6/2004 13/12/2004 1/10/2008 

Carbaglu® NAGS deficiency Orphan Europe 18/10/2000 24/1/2003 7/12/2005 21/8/2006 1/9/2006 

Duodopa® Parkinson Solvay / / 7/7/2006 16/2/2007 1/3/2007 

Elaprase® 

Mucopolysaccharidosis, type II (Hunter 

Syndrome) 

Shire 11/12/2001 8/1/2007 13/3/2007 20/12/2007 1/1/2008 

Evoltra® Acute lymphoblastic leukaemia Genzyme 5/2/2002 29/5/2006 7/1/2008 20/6/2008 1/7/2008 

Exjade® 

Chronic iron overload requiring chelation 

therapy 

Novartis Pharma 13/3/2002 28/8/2006 6/11/2006 20/6/2007 1/8/2007 

Fabrazyme® Fabry disease Genzyme 8/8/2000 4/5/2001 8/4/2002 20/7/2004 1/8/2004 

Glivec® 

Increlex® 

Chronic myeloid leukaemia 

7/7/2003 19/3/2004 

Novartis 14/2/2001 27/8/2001 

Malignant gastrointestinal stromal tumours 5/8/2002 20/6/2003 

Treatment of primary insulin-like growth factor-1 

deficiency due to molecular or genetic defects 

(primary growth hormone insensitivity syndrome) 

1/7/2003 

Ipsen 22/5/2006 3/8/2007 3/12/2007 18/7/2008 1/8/2008 

Lysodren® Adrenal cortical carcinoma HRA Pharma 12/6/2002 28/4/2004 21/11/2006 20/12/2007 1/1/2008 

Myozyme® 

Naglazyme® 

Glycogen Storage Disease type II (Pompe´s 

disease) 

Treatment of Mucopolysaccharidosis, type VI 

(Maroteaux-Lamy Syndrome) 

Genzyme 14/2/2001 29/3/2006 18/5/2006 20/4/2007 1/5/2007 

Biomarin Europe 14/2/2001 24/1/2006 21/11/2007 20/11/2008 1/12/2008


Drug Indication Sponsor EMEA NIHDI 

Nexavar® 

Orphan 

Designation 

MA 

Submission 

date 

Approval 

date 

Reimbursed 

since 

Renal cell carcinoma 

1/8/2006 21/3/2007 1/4/2007 

Bayer Healtcare 29/7/2004 19/7/2006 

Hepatocellular carcinoma 2/10/2007 20/6/2008 1/7/2008 

Orfadin® Tyrosinaemia type 1 Swedish Orphan 29/12/2000 21/2/2005 3/8/2005 20/6/2006 1/7/2006 

Replagal® Fabry disease TKT-Europe / Shire 8/8/2000 4/5/2004 Unknown Unknown 

Revatio® Pulmonary Arterial Hypertension Pfizer 12/12/2003 28/10/2005 24/5/2006 21/5/2007 1/6/2007 

Revlimid® Multiple Myelome Celgene 12/12/2003 14/6/2007 19/7/2007 21/3/2008 1/4/2008 

Savene® Anthracycline extravasations Topotarget 10/9/2001 28/7/2006 14/12/2006 21/8/2007 1/9/2007 

Somavert® Acromegaly Pfizer 14/2/2001 13/11/2002 27/6/2003 19/3/2004 1/4/2004 

Sprycel® Chronic myeloid leukaemia Bristol-Myers Squibb 23/12/2005 20/11/2006 14/12/2006 21/8/2007 1/9/2007 

Sutent® 

1/8/2004 

Malignant gastrointestinal stromal tumours 

9/8/2006 21/3/2007 1/4/2007 

Pfizer 

Renal cell carcinoma 8/2/2007 20/7/2007 1/8/2007 

Tasigna® Chronic myeloid leukaemia Novartis Pharma 13/4/2007 19/11/2007 17/12/2007 21/8/2008 1/9/2008 

Thalidomide 

® 

Multiple Myelome Celgene 20/11/2001 16/4/2008 Unknown Unknown 18/09/1999 

Thelin® Pulmonary Arterial Hypertension Pfizer / Encysive UK Ltd 21/10/2004 10/8/2006 19/4/2007 20/12/2007 1/1/2008 

Torisel® Renal cell carcinoma Wyeth 6/4/2006 19/11/2007 4/1/2008 20/11/2008 1/12/2008 

Tracleer® 

Pulmonary Arterial Hypertension 

Chronic thromboembolic pulmonary 

hypertension 

Actelion 14/2/2001 15/5/2002 

8/1/2003 20/7/2004 1/8/2004 

21/12/2005 21/8/2006 1/9/2006 

Trisenox® Acute promyelocytic leukaemia Cephalon 18/10/2000 5/3/2002 16/2/2005 20/10/2005 1/11/2005 

Xagrid® Essential thrombocytose Shire 29/12/2000 16/11/2004 24/1/2005 20/10/2005 1/11/2005 

Zavesca® Gaucher disease Actelion 18/10/2000 20/11/2002 30/11/2004 19/8/2005 1/9/2005


8.2 CHARACTERISTICS OF ORPHAN DRUGS SUBMITTED FOR REIMBURSEMENT IN BELGIUM, 2004-2008 


(ATC 

code) 

Reimbursement 

application 

Original or 

revision 

Reimbursed Number / 

design 

Therapeutic value Therapeutic needs Budget impact 

Evidence 

published 

First or 

second 

line 

Alternative Number 

of 

patients 

Cost per 

patient per 

year 

Supplier 

Aldurazyme ® 

(A16AB05) 

Revision Yes 1 RCT No First No 12 € 40,000 Genzyme 1 // 1 

Atriance ® 

Original Yes 2 case series Yes Second No 5 children, € 23,000 (adult), GSK 1 // 1 

(L01BB07) 

19 adults €14,000 (child) 

Busilvex ® 

Original No 2 open-label Yes Second Yes Pierre Fabre 1 // 0 

(L01AB01) 

studies 

Médicament 

Carbaglu ® 

Original Yes 2 case series No First No 5-6 € 14,000- Orphan Europe 1 // 1 

(A16AA05) 

1,100,000 

Duodopa ® 

(N04BA02) 

Original Yes 2 case series No First Yes 80 € 41,000 Solvay Pharma 0 // 1 

Elaprase ® 

(A16AB09) 

Original Yes 1 RCT Yes First No 13 € 300,000 Shire 1 // 1 

Exjade ® 

Original Yes 1 RCT, 1 Yes First / Yes 450-1,150 € 12,000-23,000 Novartis pharma 1 // 1 

(V03AC03) 

case series 

second 

Fabrazyme ® 

Revision Yes 2 RCTs, 3 Yes First Yes 50-75 € 195,000€ Genzyme 1 // 1 

(A16AB04) 

case series 

Glivec ® 

Original No First / No € 48,000 Novartis 6 // 2 

(L01XE01) 

second 

Lysodren ® 

Original Yes Case series No First No 36 € 167,000 Laboratoire 1 // 1 

(L01XX23) 

HRA Pharma 

Myozyme ® 

Original Yes 2 open-label No First No 24 children, € 55,000- Genzyme 1 // 1 

(A16AB07) 

studies, 2 

case series 

51 adults 328,000€ 

Nexavar ® 

(L01XE05) 

Original Yes 1 RCT Yes Second Yes 120 € 50,000 Bayer Healthcare 2 // 1 

Orfadin ® Original Yes Case series No First Yes 11 € 100,000 Swedish Orphan 1 // 1 

Number of 

indications 

(EMEA // 

Belgium)



(ATC 

code) 

Reimbursement 

application 

Therapeutic value Therapeutic needs Budget impact 

Supplier 

(A16AX04) International 

Replagal ® 

(A16AB03) 

Revision Yes 3 case series No First Yes 50-75 € 200,000 Shire EGT 1 // 1 

Revatio ® 

Original Yes 2 RCTs Yes First / Yes 105 € 7,000-26,000 Pfizer 2 // 1 

(G04BE03) 

second 

Revlimid ® 

(L04AX04) 

Original Yes 2 RCTs No Second Yes 200 € 60,000 Celgene 1 // 1 

Savene ® 

(V03AF02) 

Original Yes 2 case series No First No 29 € 10,000 Topotarget 1 // 1 

Somavert ® 

(H01AX01) 

Original Yes 1 case series Yes Second No 70 € 47,000 Pfizer 1 // 1 

Sprycel ® 

(L01XE06) 

Original Yes 6 case series Yes Second Yes 85 € 56,000 Bristol-Myers 2 // 1 

Sutent ® 

Original Yes 1 RCT No Second Yes 73 € 16,000 Pfizer 2 // 2 

(L01XE04) Original Yes 2 case series Yes Second Yes 180-240 € 20,000 

Thelin ® 

Original Yes 3 RCTs No First / Yes 300 € 32,000 Encysive 2 // 2 

(C02KX03) 

second 

Tracleer ® 

Original Yes 2 RCTs No First Yes 300 € 40,000 Actelion 2 // 2 

(C02KX01) 

Registration ltd 

Trisenox ® 

(L01XX27) 

Original Yes 2 case series Yes Second No 9 €37,000 Cephalon 1 // 1 

Wilzin ® 

(A16AX05) 

Original No Yes Orphan Europe 1 // 0 

Xagrid ® 

Original Yes 6 case series Yes Second No 1,100 €8,000 Shire 

1 // 1 

(L01XX35) 

Pharmaceutical 

Zavesca ® 

Original Yes 1 open-label Yes Second Yes 90 € 93,000 Actelion 1 // 1 

(A16AV06) 

study, 2 case 

series 

Number of 

indications 

(EMEA // 

Belgium)


8.3 QUALITATIVE QUESTIONNAIRE BENCHMARKING 

Country Name: 

Name: 

Title: 

Institution: 

Address: 

Country: 

Telephone: 

Fax: 

Email: 

THE RARE DISEASE AND ORPHAN DRUG MARKET: 

Questionnaire 

Instructions: Please respond to questions electronically. You can move forward 

through the main body of the questionnaire by pressing "Tab" and backwards by 

pressing "Shift + Tab", or you can use the scroll feature and the mouse. Boxes can be 

ticked and ticks can be removed by double-clicking the mouse. 

Identification 

Contact Details for the Person Completing the Form 

Correspondence address: 

Christel Fostier 

Yellow Window Management Consultants 

Lange Lozanastraat 254 

2018 Antwerpen 

Belgium 

T: +32/3/241.00.24 

F: +32/3/203.53.03 

E: Christel.Fostier@yellowwindow.com 

Section 1. Institutional context of orphan diseases/orphan drugs 

1.1. Identify and list centres for orphan diseases: 

1.2. Identify and list policy measures that promote specifically the development of orphan drugs: 

1.3. Identify and list specific programmes to fund research networks on orphan diseases and on orphan drugs: 

1.4. Identify and list incentives for research on orphan diseases and on orphan drugs: 

1.5. Any additional comments on the institutional context surrounding orphan diseases and orphan drugs: 

1.6. Are thresholds defined for reimbursement decisions for drugs expressed in 

QALY or similar? 

.a If "Yes", what is the threshold: 

Yes: No:


.b Is this threshold also applied for orphan drugs? Or a different threshold? Yes: No: 

.c If a different threshold is used, which one: 

.d Do you expect changes in this regard in the short to medium term? Yes: No: 

.e If yes, please explain: 

1.7. Is there a national definition for “orphan disease” and/or “ultra-rare 

disease”? 

.a If “Yes”, give the definition and its source: 

Section 2. Marketing Authorisation of orphan drugs 

2.1. Is there a national procedure for granting Marketing Authorisation of 

orphan drugs instead of the EMEA procedure? If "No", go to 

question 2.2. 

Yes: No: 

Yes: No: 

.a If "Yes", name the organisation in charge of the national procedure for Marketing Authorisation: 

.b If “Yes”, specify how long it takes to obtain a Marketing Authorisation (i.e. the duration of the application 

procedure): 

.c If “Yes”, specify the various criteria that are used to judge an application: 

2.2. Is there a procedure for compassionate use of orphan drugs? 

If "No", go to question 2.3. 

.a If "Yes", specify the various criteria for compassionate use of orphan drugs: 

2.3. Is there a procedure for off-label use of orphan drugs? 


.a If "Yes", specify the various criteria for off-label use of orphan drugs: 

2.4. Any additional comments on Marketing Authorisation of orphan drugs: 

Yes: No: 

Yes: No:


Section 3. Pricing of orphan drugs 

3.1. Describe the mechanism by which prices of orphan drugs are set: 

.a Free market pricing: 

If "Yes", describe system of free market pricing: 

Yes: No: 

.b Fixed pricing: 

If "Yes", describe system of price fixing: 

Yes: No: 

.c Other (please specify): Yes: No: 

3.2. 

Describe the principal bodies or agencies that are involved in pricing of orphan drugs: 

3.3. Is there a procedure for revising prices of orphan drugs on 

national/regional lists? If "No", go to question 3.4. 

Yes: No: 

.a If "Yes", describe which factors are taken into account when revising prices (e.g. change in production 

costs, evolution of price index): 

.b If “Yes”, indicate how often prices are revised: 

3.4. Any additional comments on pricing system of orphan drugs: 

Section 4. Reimbursement of orphan drugs 

4.1. Describe the mechanism by which reimbursement of orphan drugs is set: 

.a Public procurement at national level: 

If "Yes", describe system of tendering: 

Yes: No: 

.b Public procurement at regional/local level: 

If "Yes", describe system of tendering: 

Yes: No: 

.c National list of tariffs: 

If "Yes", specify how tariffs are set: 

Yes: No: 

Also, specify name of national list: 

.d Regional list of tariffs: Yes: No: 

If "Yes", specify how tariffs are set: 

Also, specify name of regional list: 

.e Other (please specify): Yes: No: 

4.2. Which third-party payer reimburses orphan drugs? 

National Health Service 

.a (tick appropriate box) 

Social insurance: 

Public 

Private 

Combination 

.b Describe the process and decision criteria that are used for admitting a new orphan drug to the system of 

third-party payer reimbursement: 

.c Describe the process and decision criteria that are used for determining the level of third-party payer 

reimbursement of a new orphan drug: 

.d Are there any restrictions/conditions for reimbursement of orphan Yes: No:


drugs? 

If "Yes", describe restrictions/conditions: 

.e Specify the level of patient co-payments for orphan drugs: 

4.3. Any additional comments on reimbursement system of orphan drugs: 

4.4. Is the reimbursement decision based on the EMEA dossier and/or the ICH report? If “Yes”, please describe 

how these documents are used: 

Section 5. Distribution channels 

5.1. Describe principal bodies or agencies that dispense orphan drugs to patients: 

.a Hospital pharmacies: Yes: No: 

.b Community pharmacies: Yes: No: 

.c Health authorities: Yes: No: 

.d Internet: Yes: No: 

.e Other (please specify): Yes: No: 

Section 6. Prescribing process 

6.1. Describe the mechanism by which orphan drugs are prescribed: 

.a Which party issues the first prescription? (tick one or more 

appropriate boxes) 

.b Are there any conditions for prescribing orphan drugs? 


If "Yes", describe conditions: 

6.2. Is there any control mechanism? Yes: No: 

If “Yes”, please describe this control mechanism: 

Specialist physician 

Nurse practitioner 

General practitioner 

Yes: No: 

6.3. Are there differences in individual reimbursement decisions depending on: 

Region Yes: No: 

Orphan drug Yes: No: 

Other: Yes: No: 

Please describe these differences: 

6.4. Any additional comments on prescribing process of orphan drugs: 

Thank you for your assistance 

Please return questionnaire by e-mail to: 

Christel.Fostier@yellowwindow.com


8.4 QUALITATIVE QUESTIONNAIRE PHARMACEUTICAL 

INDUSTRIES 

Questionnaire 

Study “Orphan Diseases and Orphan Drugs” 

Contact details for the person completing the form 

Name: 

Title: 

Institution: 

Address: 

Country: 

Telephone: 

Fax: 

Email: 

Correspondence address: 

Christel Fostier 

Yellow Window Management Consultants 

Lange Lozanastraat 254 

2018 Antwerpen 

Belgium 

T: +32/3/241.00.24 

F: +32/3/203.53.03 

E: christel@yellowwindow.com 

1. Pros and cons of the system of orphan drug based on experience with this specific drug 

a. Pros: 

b. Cons: 

2. Orphan Designation 

a. The designation is acquired if the medical product fulfils one of the prevalence 

following criteria: either / or prevalence versus economic motives. 

Which criterion was used in this case? 

economic 

b. Has anything changed since the designation in this respect (either prevalence or economic) 

3. FDA versus EMEA 

a. Is the situation for this drug different in the USA and EU or is it 

likewise? 

b. If different, what are those differences? 

4. Post-Marketing Authorisation 

a. Have you obtained MA under exceptional circumstances or a 

conditional MA? 

i. If exceptional or conditional, under what conditions: 

ii. What is the actual status? (Still exceptional/conditional?) 

different 

same 

exceptional 

conditional 

none


b. Have you set up a patient register? yes 

no 

i. Is this imposed or is it a free decision? 

ii. Who is managing the register? 

yes 

no 

5. Post-reimbursement 

a. Forecast of number of patients done at start versus actual number of patients 

identified: ……… versus ……… 

b. Forecast budget impact versus actual budget impact: ……… versus ……… 

c. How did you experience the interaction with the College of Orphan Drugs? 

d. Do all patients have access or do you notice that patients face 

barriers to get access? 

i. What types of barriers are faced? 

all have access 

barriers 

ii. If applicable: how many / what is the proportion of patients that do not have 

access? ……… 

e. Do you consider that conditions imposed to obtain reimbursement yes 

are adequate? 

i. If not, in what sense? Has or is this changing overtime? 

no 

ii. Who plays a leading role in changing/adapting those conditions/rules? 

6. Present situation: could you fill in the table below for following questions 

a. How many patients are there in each country? 

b. What is the price of the drug in following countries? 

c. What is the turnover in each country? 

Belgium France Netherlands 

UK Italy Sweden 

Number of patients 

Price 

Turnover 

Date of market 

introduction 

d. Do you consider all patients to have been identified or do you expect the number of 

patients to grow? (in Belgium) 

Thank you for your assistance 

Please return questionnaire by e-mail to: 

christel@yellowwindow.com


8.5 LIST OF EXPERTS AND STAKEHOLDERS CONSULTED 

FOR THE STUDY 

8.5.1 List of interview respondents 

Respondent Institution Date 

Dr Ségolène Aymé Orphanet 4/7/2008 

Mr André Lhoir Federal Agency for Medicines and Health Product 

(Belgium) 

12/9/2008 

Mr Marc Dooms UZ Leuven (Belgium) 30/9/2008 

Dr David Cassiman UZ Leuven (Belgium) 30/9/2008 

Mr Daniel Brasseur EMEA 1/10/2008 

Mr Erik Tambuyzer Genzyme 7/10/2008 

Mr Erik Brouwer 

Ms Katrien Van Geyt 

Ms Annemie Mertens 

Genzyme 20/10/2008 

Dr Jordi LLinares EMEA 14/11/2008 

Mr Alastair Kent Genetic Interest Group (United Kingdom) 20/11/2008 

Ms Françoise Marlier FPS Economy (Belgium) 12/2/2009 

Mr François Arickx NIHDI (Belgium) 13/2/2009 

Ms Minne Casteels NIHDI (Belgium) 16/2/2009 

Mr Michael Berntgen EMEA 18/2/009 

Mr Philippe Van Wilder NIHDI (Belgium) 2/4/2009 

Mr Paul De Keyser Independent consultant for pharmaceutical 

industries 

8.5.2 Consultations 

7/4/2009 

Consultation and exchanges took place with the Fund Rare Diseases and Orphan Drugs 

of King Baudouin Foundation (Belgium), including participation in their meetings on the 

19 th of September and 14 th of October 2008. 

A consultation took place with Pharma.be on the 7 th of April 2009: presentation of the 

study and consultation on the main issues. 

8.5.3 National experts 

• France: Mrs Annie Lorence of the Afssaps 

• Italy: Dr Pierre Folino Gallo of the Italian Medicines Agency 

• Netherlands: Dr Sonja Van Weely of the Dutch Steering Committee 

Orphan Drugs 

• Sweden: Mr Karl Arnberg of the Dental and Pharmaceutical Benefits 

Board 

• United Kingdom: Ms Martina Garau of the Office of Health Economics


8.6 LIST OF 14 ORPHAN DRUGS USED FOR EMEA – NIHDI 

COMPARISON 

1. Aldurazyme ® 

2. Atriance ® 

3. Elaprase ® 

4. Fabrazyme ® 

5. Nexavar ® (for indications RCC and HCC) 

6. Replagal ® 

7. Revatio ® 

8. Revlimid ® 

9. Sprycel ® 

10. Tasigna ® 

11. Tracleer ® 

12. Trisenox ® 

13. Xagrid ® 

14. Zavesca ®


9 REFERENCES 

1. Casteels M, Van Wilder P, Arickx F. De rol van de Commissie Tegemoetkoming 

Geneesmiddelen in het geneesmiddelenbeleid. In: Vorming verzekeringsgeneeskunde. 

Wetenschappelijke Vereniging voor Verzekeringsgeneeskunde; 2007. 

2. Drummond M, David F, Wilson A, Kanavos P, Ubel P, Rovira J. Assessing the economic 

challenges posed by orphan drugs. International Journal of Technology Assessment. 

2007;23(1):36-42. 

3. Van Weely S, Leufkens H. Orphan diseases. In: Priority Medicines for Europe and the World 

"A Public Health Approach to Innovation"; 7 October 2004. Available from: 

4. 

http://mednet3.who.int/prioritymeds/report/index.htm 

Veeken H, Pécoul B. Drugs for ‘neglected diseases’: a bitter pill. Tropical Medicine and 

International Health. 2000;5(5):309-11. 

5. Regulation (EC) No 141/2000 of the European Parliament and the Council of 16 December 

1999 on orphan medicinal products, 2000. 

6. Australian orphan drugs policy 1997. 

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47. Organisation for Economic Co-operation and Development. Health at a glance 2007: OECD 

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48. Denis A, Mergaert L, Fostier C. Organisation and financing of genetic testing in Belgium. Health 

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49. Stuurgroep Weesgeneesmiddelen. Available from: www.weesziekten.be 

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52. Koninklijk Besluit van 21 december 2001 tot vaststelling van de procedures, termijnen en 

voorwaarden inzake de tegemoetkoming van de verplichte verzekering voor geneeskundige 

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from: http://ec.europa.eu/enterprise/pharmaceuticals/register/orphreg.htm 

54. Wet houdende herziening van de farmaceutische wetgeving, 1/5/2006. 

55. Trouet C, Gobert M, Podoor M. Clinical Trials in Belgium: The Belgian implementation of the 

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56. Wet van 27/4/2005 betreffende de beheersing van de begroting van de gezondheidszorg en 

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België Brussels; 7 December 2006. 

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Maladies Orphelines. Available from: http://www.sante-sports.gouv.fr/dossiers/sante/maladiesrares/maladies-rares.html?var_recherche=orphelin 

62. Lorence A. Les médicaments orphelins en Europe. In: Afssaps, editor. MEDEC; 15/03/2006. 

63. Meyer F. Orphan Drugs: How Are They Assessed / Appraised in France? In: HAS, editor. 25 

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64. Meyer F. Assessment, Pricing of Pharmaceuticals in France. In: AIFA. Rome; March 2007. 

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68. Seget S. Pharmaceutical Pricing Strategies: Optimizing returns throughout R&D and marketing. 

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72. Folino Gallo P. Orphan Drugs in Italy. Accommodating orphan drugs: balancing innovation and 

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78. College ter Beoordeling van Geneesmiddelen. Off-label use. Available from: http://www.cbgmeb.nl/CBG/nl/humane-geneesmiddelen/geneesmiddelen/Off-label-use/default.htm 

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96. Garau M, Chauhan D. Decision-making processes in the orphan drugs arena. The UK 

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99. Garau M, Mestre-Ferrandiz J, Wang Q. Access Mechanisms for Orphan Drugs: A Comparative 

Study of Selected European Countries. London: Office of Health Economics; Forthcoming. 

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101. WHO Collaborating Centre for Drug Statistics Methodology. Anatomical Therapeutic 

Chemical classification system for drugs. Available from: http://www.whocc.no 

102. RIZIV;c 1/3/2009. Farmaceutische specialiteiten. Available from: 

http://www.riziv.fgov.be/inami_prd/ssp/cns2/pages/SpecialityCns.asp 

103. RIZIV (Dienst voor Geneeskundige Verzorging). Monitoring Of Reimbursement Significant 

Expenses. M.O.R.S.E. semesterieel rapport 2008 (1) gegevens 1e semester 2008. RIZIV; 2008. 

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104. European Organisation for Rare Diseases. EURORDIS Position Paper on the “Centralised 

procedure for the scientific assessment of the Therapeutic Added Value of Orphan Drugs”. 

February 2008. Available from: http://www.eurordis.org/IMG/pdf/position-paper-EURORDIStherapeutic-added-value-ODFeb08.pdf 

105. Working Group Pricing and Reimbursement. Improving access to orphan medicines for all 

affected EU citizens. In: The Pharmaceutical Forum, editor.; 2008. 

106. Connock M, Juarez-Garcia A, Frew E, Mans A, Dretzke J, Fry-Smith A, et al. A systematic 

review of the clinical effectiveness and cost-effectiveness of enzyme replacement therapies for 

Fabry’s disease and mucopolysaccharidosis type I. Health Technology Assessment. 2006;10(20).

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Legal depot : D/2009/10.273/32

KCE reports 

33 Effects and costs of pneumococcal conjugate vaccination of Belgian children. D/2006/10.273/54. 

34 Trastuzumab in Early Stage Breast Cancer. D/2006/10.273/25. 

36 Pharmacological and surgical treatment of obesity. Residential care for severely obese children 

in Belgium. D/2006/10.273/30. 

37 Magnetic Resonance Imaging. D/2006/10.273/34. 

38 Cervical Cancer Screening and Human Papillomavirus (HPV) Testing D/2006/10.273/37. 

40 Functional status of the patient: a potential tool for the reimbursement of physiotherapy in 

Belgium? D/2006/10.273/53. 

47 Medication use in rest and nursing homes in Belgium. D/2006/10.273/70. 

48 Chronic low back pain. D/2006/10.273.71. 

49 Antiviral agents in seasonal and pandemic influenza. Literature study and development of 

practice guidelines. D/2006/10.273/67. 

54 Cost-effectiveness analysis of rotavirus vaccination of Belgian infants D/2007/10.273/11. 

59 Laboratory tests in general practice D/2007/10.273/26. 

60 Pulmonary Function Tests in Adults D/2007/10.273/29. 

64 HPV Vaccination for the Prevention of Cervical Cancer in Belgium: Health Technology 

Assessment. D/2007/10.273/43. 

65 Organisation and financing of genetic testing in Belgium. D/2007/10.273/46. 

66. Health Technology Assessment: Drug-Eluting Stents in Belgium. D/2007/10.273/49. 

70. Comparative study of hospital accreditation programs in Europe. D/2008/10.273/03 

71. Guidance for the use of ophthalmic tests in clinical practice. D/200810.273/06. 

72. Physician workforce supply in Belgium. Current situation and challenges. D/2008/10.273/09. 

74 Hyperbaric Oxygen Therapy: a Rapid Assessment. D/2008/10.273/15. 

76. Quality improvement in general practice in Belgium: status quo or quo vadis? 

D/2008/10.273/20 

82. 64-Slice computed tomography imaging of coronary arteries in patients suspected for coronary 

artery disease. D/2008/10.273/42 

83. International comparison of reimbursement principles and legal aspects of plastic surgery. 

D/200810.273/45 

87. Consumption of physiotherapy and physical and rehabilitation medicine in Belgium. 

D/2008/10.273/56 

90. Making general practice attractive: encouraging GP attraction and retention D/2008/10.273/66. 

91 Hearing aids in Belgium: health technology assessment. D/2008/10.273/69. 

92. Nosocomial Infections in Belgium, part I: national prevalence study. D/2008/10.273/72. 

93. Detection of adverse events in administrative databases. D/2008/10.273/75. 

95. Percutaneous heart valve implantation in congenital and degenerative valve disease. A rapid 

Health Technology Assessment. D/2008/10.273/81 

100. Threshold values for cost-effectiveness in health care. D/2008/10.273/96 

102. Nosocomial Infections in Belgium: Part II, Impact on Mortality and Costs. D/2009/10.273/03 

103 Mental health care reforms: evaluation research of ‘therapeutic projects’ - first intermediate 

report. D/2009/10.273/06. 

104. Robot-assisted surgery: health technology assessment. D/2009/10.273/09 

108. Tiotropium in the Treatment of Chronic Obstructive Pulmonary Disease: Health Technology 

Assessment. D/2009/10.273/20 

109. The value of EEG and evoked potentials in clinical practice. D/2009/10.273/23 

111. Pharmaceutical and non-pharmaceutical interventions for Alzheimer’s Disease, a rapid 

assessment. D/2009/10.273/29 

112 Policies for Rare Diseases and Orphan Drugs. D/2009/10.273/32. 

This list only includes those KCE reports for which a full English version is available. However, all KCE 

reports are available with a French or Dutch executive summary and often contain a scientific 

summary in English.

Policies for Rare Diseases and Orphan Drugs - KCE

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